Coagulation disorders – pulmonary
embolism
MUDr. Tamara Skříšovská
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1. Haemostasis
Haemostasis is defined as a balance to maintain the fluidity of blood vessels while forming a hemostatic
plug, in case of vascular injury. The result of this process is fibrin which traps the blood cells in the bloodforming
clot. It is academically divided into different steps but most of them are happening simultaneously in
vivo:
A. Vasoconstriction
B. Primary haemostatic plug
I. Adhesion
II. Activation and secretion
III. Aggregation
C. Secondary hemostasis-coagulation cascade
I. Initiation- extrinsic pathway+ common pathway
II. Amfiplication- intrinsic pathway+ common pathway
III. Propagation
D. Regulation
• Antiagregation
• Anticoagulation
• Fibrynolytics
(a) Vasoconstriction
Represents a local response aiming to stop the bleeding and facilitate platelet adhesion. Substances that
are primarily involved in the vessel vasoconstrictions are endothelin, serotonin (5-HT) from endothelium and
thromboxane (TXA) from platelets.
(b) Primary haemostatic plug
The creation of a primary plug is initiated by collagen exposed by damaged vessel endothelium, this causes
a platelet activation (role of von Willebrand factor) and degranulation (granules containing- adenosine
diphosphate (ADP), serotonin, thromboxane A, factor V, factor XIII, fibrinogen). This leads to enhanced
vasospasm and aggregation of more platelets.
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(c) Secondary hemostasis - coagulation cascade
Taking it from the end. What do we want to achieve? The goal is to end up with fibrin stabilizing the primary
plug. This happens through activating FIBRINOGEN into FIBRIN (which can polymerase and form the
stabilizing mesh), this step is mediated by Thrombin (f IIa).
The coagulation cascade
The coagulation cascade is a series of enzymatic reactions that turn inactive precursors into active factors.
The result of the cascade is the production of fibrin, a protein that binds platelets and other materials in a
stable clot.
There is the "classic model" which is more applicable in vitro. We need to understand it to be able to interpret
the laboratory tests and imagine the effects of drugs. In this model, the cascade has two initial pathways:
the extrinsic (tissue factor-mediated) and the intrinsic (contact system-initiated). These two pathways
converge to become the common pathway with the activation of factor X.
In extrinsic the damaged vessel releases the tissue factor (f III) and this together with factor VII (f VII), which
circulates in the blood, activates factor X (f Xa).
In the intrinsic pathway, where factor XII is activated by kallikrein, the cascade gradually activates factors XI,
IX and VII to activate factor X.
The common pathway starts by activating factor X, which in combination with Ca2+ ions and activated factor
V (thromboxane) causes the desirable activation of factor II (prothrombin), activating it to thrombin (f IIa).
Thrombin acts by changing fibrinogen into fibrin. An important plug stabilizing factor is XIII.
Figure 1: Coagulation cascade and its physiological regulators
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Evidence supports the understanding that the intrinsic pathway is not a parallel but it augments thrombin
generation primarily initiated by the extrinsic pathway. More physiological is the cellular model (“in vivo
model”) of coagulation, which includes:
I. Initiation phase
Tissue injury and collagen exposure (tissue factor) is called an extrinsic pathway. Initiated when prothrombin
is activated to thrombin (f IIa), this is called an initial thrombin burst.
II. Amplification stage
Factor IIa does all the job, it activates fibrinogen to fibrin, activates intrinsic pathway and activates cofactors
(f V, f VIII-f IX, f XIII).
(d) Regulation
The clotting mechanism is balanced by opposing reactions.
• In primary haemostasis the physiological antiaggregatory agents (endotheliumprostaglandins-PG2-
NO, heparin sulphate)
• In secondary haemostasis the physiological anticoagulants (Tissue factor platelet inhibitorTFPI,
Antithrombin-AT, protein C, S)
• System to dissolve the clot
• tPA (tissue plasmin activator) activates plasminogen to plasmin which cuts the fibrin mesh
creating the fibrin degradation products (FDP), one of the fibrin degradation products is D-dimers
Figure 2: Factors favouring and inhibiting thrombosis
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Drugs affecting the coagulation system
1. Antiaggregant/antiplatelets
I. COX 1 inhibitors- non-steroidal anti-inflammatory drugs-(NSAID´s), acetylsalicylic acid
(ASA)
II. P2Y12 ADR receptor inhibitors –Clopidogrel, Prasugrel (both p.o)
Both are irreversible inhibitors of the platelet P2Y12 adenosine diphosphate receptor (ADR). Inhibition of this
receptor prevents the downstream activation of the glycoprotein IIb/IIIa receptor complex, which leads to
reduced platelet aggregation.
III. Glycoprotein IIb/IIIa (membrane of platelets) inhibitor –Abciximab, Tirofiban (i.v.)
2. Anticoagulants
I. Heparin
Chemically it is a mixture of polysaccharides. Heparin binds to antithrombin, increasing its effect by 1000 x.
• unfractionated (UFH)- extracted from pig gastric mucosa, binds to antithrombin, causing its
conformational change, half time 90 min, possible antagonist protamine (1mg protamine to 100 IU
UFH), monitor by using aPTT (aim 1,5-2,5 x normal aPTT), risk of heparin-induced
thrombocytopenia (HIT)
• low molecular weight heparin (LMWH) -enoxaparin, dalteparin- produced by enzymatic/ chemical
degradation of heparin, better bioavailability, longer half time (1x daily s.c), greater activity against
Xa also partially affects f IIa, cause less inhibition of platelet function (less HIT risk), renal excretion
(dosage reduction in renal failure), cannot be completely neutralized by protamine
• fondaparinux- synthetic pentasaccharide, an indirect inhibitor of f Xa, contraindicated in severe
acute kidney injury, can be used in HIT
II. vitamin K antagonists- coumarins
Warfarin inhibits the enzyme vitamin K epoxide reductase, blocking the hepatic synthesis of the
active, reduced form of vitamin K. Vitamin K-dependent coagulation factors are II, VII, IX, X and protein C,
protein S. When warfarin is used regular monitoring is necessary. This is done by prothrombin time PT/
international normalized ratio INR (goal INR of 2 to 3) extrinsic pathway of the coagulation cascade. Warfarin
interacts with a broad range of medications and food (metabolization by C-P450). Substances that increase,
or decrease the effect of warfarin are summoned here:
https://www.remedirx.com/wp-content/uploads/2016/06/Warfarin-DDI-Reference_Bimonthly-Resource-
FINAL-061716.pdf.
It is not suitable for acute therapy of PE or DVT. In case of extensive or life-threatening bleeding: stop
coumarins; administer fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) and vitamin K
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III. Non-vitamin K antagonist oral anticoagulants (NOACs)
• Direct thrombin inhibitors- dabigatran (Pradaxa)
• Factor X inhibitors- rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa)
In comparison to warfarin, NOACs have more predictable pharmacokinetics, fewer drug interactions, shorter
half-lives, and quicker onset of action. Factor Xa catalyses the activation of prothrombin into thrombin, all
NOACs exert an anti-thrombin effect and prevent the activation of fibrinogen into fibrin. They do not require
regular monitoring but also lack routine tests for monitoring. For the events of life-threatening haemorrhage,
specific antidotes are available (idarucizumab- PRAXBIND is a dabigatran antidote and andexanet alfa for
factor Xa inhibitors, Aripazine is a new universal NOAC antidote that binds to both factor Xa inhibitors and
dabigatran through hydrogen bonds- phase 2 trials are ongoing). NOACs are not suitable for patients with
artificial valves.
IV. Thrombolytic agents
• Recombinant tissue-type plasminogen activator (tPA- alteplase), streptokinase (SK),
recombinant human urokinase (UK), alteplase – has a high affinity to fibrin, binds to coagulum
and in the presence of fibrin activates plasminogen to plasmin, half-life time is 5 minutes.
Figure 3: Drugs affecting the coagulation cascade
Laboratory testing
Used to identify patients at risk of bleeding or thrombosis or to effectively monitor/manage the treatment. In
emergencies (e.g., life-threatening bleeding- rapid) changes in laboratory values could be established by
bedside tests.
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Prothrombin time (PT)
• measures the time it takes plasma to clot when exposed to tissue factor and phospholipid in
recalcified citrated patient plasma,
• assess extrinsic pathway (II, V, VII, IX) and common pathway
• the result is measured in seconds, normal range of 11- 15 s
• INR international normalised ratio (patient’s PT to a control PT), normal range 0,7-1,2
prolonged e.g., in warfarin therapy
Activated partial thromboplastin time (APTT)
• measures time to clot formation when citrated plasma is exposed to negatively charged substances
(e.g., kaolin), prothromboplastin and calcium
• assesses the intrinsic and common pathways of coagulation
• prolonged e.g., in heparin therapy, haemophilia A, B, von Willebrand disease
• normal range 26-40s
• another option for monitoring full-dose unfractionated heparin is to use anti-factor Xa activity
(sometimes called "anti-Xa")
Thrombin time (TT)
• measures the final step of coagulation, the conversion of fibrinogen to fibrin
• citrated plasma in the presence of thrombin
• prolonged if fibrinogen levels are low or if an anticoagulant that inhibits thrombin is present in the
sample
• not routinely used
• heparin, LMWH, direct thrombin inhibitors (e.g., bivalirudin or argatroban) prolong
• in contrast, oral direct Xa inhibitors, danaparoid, fondaparinux, and warfarin do not prolong TT
• normal range 14-19 s
plasma anti-Xa – monitor LMWH effect
Table 1: Clotting times, platelets, and fibrinogen changes in different clinical situations
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Fibrinogen
• precursor of fibrin
• abnormally low levels can result in impaired clot formation and increased bleeding
risk
• 1,5-4,0 g/l
D-dimers
• fibrin degradation product (or FDP), a small protein fragment
present in the blood after a blood clot is degraded by fibrinolysis
• high negative predictive value in PE
• normal range 0-0,5 g/l
• elevated also postoperatively, after trauma, in pregnancy and
elderly
ROTEM/TEG
• viscoelastic measurement of haemostasis testing
• point of care, “bed-side” method
• INTEM, EXTEM, and FIBTEM for different
coagulation pathways
Examples of thrombelastography and therapeutic suggestions source:
Example of ROTEM machine,
source:
https://www.werfen.com/na/en/c
oagulation-testing-rotem-delta
https://litfl.com/thromboelastogram-teg/
https://www.emra.org/emresident/article/teg-and-
rotem
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Inherited bleeding disorders
Haemophilia A
• X-linked recessive bleeding disorder
• a chromosomal mutation resulting in a deficiency or absence of coagulation factor VIII
• varying severity, clinical presentation: spontaneous, postoperative, or posttraumatic bleeding,
bleeding into joints, soft tissue
• prevalence of about 1 in 5000 live male births
• initial diagnostic testing: coagulation profile (prothrombin time/INR, activated partial thromboplastin
time (aPTT), platelet count, and a von Willebrand factor assay) all of which are all usually normal in
haemophilia except the aPTT which is often prolonged in moderate-to-severe disease
• factor VIII has a half-life time about 12 hours-> must be administrated 2x daily to maintain therapeutic
levels
• synthetic vasopressin(desmopressin) i.v, s.c or intranasally causes a 3-5 x increase in factor VIII
(useful in mild haemophilia not in severe cases)
• complications:
- synovitis and arthropathy secondary to recurrent hemarthrosis
- delayed post-traumatic bleeding
- increased risk of intracranial haemorrhage
- development of fVIII antibodies (difficult management, even high doses of
factor VIII may not be clinically significant)
Haemophilia B
• hereditary X-linked chromosomal disorder
• deficiency or absence of coagulation factor IX
• varying severity
• spontaneous, postoperative, or posttraumatic bleeding, bleeding into joints, soft tissue
• incidence is 1 in 20,000 to 1 in 30,000 live male births
• family history of haemophilia in 70% of cases
• initial diagnostic testing: coagulation profile (prothrombin time/INR, activated partial
thromboplastin time (aPTT), platelet count, and a von Willebrand factor assay) all of which are
all usually normal in haemophilia except the aPTT which is often prolonged in moderate-tosevere
disease
• definitive testing: factor IX activity
• complications: hemophilic arthropathy (the result of chronic synovitis and hemarthrosis)
- increased risk of intracranial haemorrhage
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Von Willebrand Disease
• bleeding disorder caused by quantitative or qualitative defects in von Willebrand factor (vWF)
activity (plays a role in platelet adhesion to damaged subendothelium as well as in stabilizing
factor VIII in plasma)-> defective platelet function, factor VIII deficiency
• vWD is the most common inherited bleeding disorder (prevalence of 0.1%-1% in the general
population)
• 3 types- different severity
• laboratory tests showing abnormalities in von Willebrand factor and/or factor VIII
• clinical presentation: mucocutaneous bleeding (gingiva, nose-epistaxis, oral and gastrointestinal
mucosa, menorrhagia, GI bleeding), ecchymoses, hematomas, and/or petechiae, haemarthrosis
is rare
Acquired bleeding disorders
Vitamin K deficiency
• f II, VII, IX, X, protein C, protein S
• deficiency due to: inadequate stores, malabsorption, oral anticoagulant drugs
• test: PT and APTT prolonged
• clinical presentation: bruising, haematuria, gastrointestinal or cerebral bleeding
Haemorrhagic disease of newborn (1 mg i.m.- vit. K to newborns)
Liver disease
• vitamin K deficiency (intra/extrahepatic cholestasis)
• reduce the synthesis of coagulation factors
• thrombocytopenia (hepatosplenomegaly, portal hypertension/ folic acid deficiency)
• functional abnormalities in fibrinogen and platelets
DIC
• a syndrome characterized by systemic intravascular
coagulation with loss of localization (activation of blood
coagulation, which generates intravascular thrombin and
fibrin, resulting in the thrombosis of small- to mediumsized
vessels) and ultimately organ dysfunction and
severe bleeding
• microthrombi formation, platelet consumption, and
subsequent exhaustion of all clotting factors, which
causes hemorrhagic manifestations
• a mixture of initial thrombosis followed by a bleeding
tendency
Figure 4: DIC pathogenesis
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• hypercoagulation and hyperfibrinolysis
• causes: malignant disease, septicemia (e.g., G- or meningococcal infection), haemolytic
transfusion reactions, obstetric causes (e.g., placental abruption, amniotic fluid embolism),
trauma, burns, surgery, acute pancreatitis, snake bite...
• clinical features depend on severity: acutely ill patient in shock, bleeding (epistaxis,
venepuncture, ecchymosis, haematuria, hemoperitoneum, hemothorax...), thrombotic
manifestation (neurological dysfunction-altered mental state, acute renal failure-oliguria,
hemoptysis, pulmonary thromboembolism, purpura fulminans - skin necrosis...)
• in severe cases prolonged PT, APTT, TT, low fibrinogen levels, high levels of fibrin degrading
products (e.g., D-dimer)
• therapy: treatment of the underlying cause, supportive therapy with transfusions of platelet
concentrates, FFP, and/or cryoprecipitate in patients with severe bleeding
• therapeutic doses of heparin should be considered in cases of DIC in which thrombosis
predominates
Inherited prothrombic disorders
I. Venous:
Leiden mutation (factor V mutation)
Antithrombin (AT) deficiency
Protein C deficiency
Protein S deficiency
II. Arterial:
Antiphospholipid antibody syndrome
▪ autoimmune disease, idiopathic or acquired (SLE, acute infection e.g., malaria, medication
e.g., phenytoin)
▪ circulating antibodies deactivate anticoagulant proteins and activate platelets -> paradox of prolonged
clotting times and prothrombotic tendency
▪ clinical presentation:
- recurrent fetal loss in 2nd or 3rd trimester
- thrombocytopenia
- skin lesions
- haemolytic anaemia
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Acquired prothrombotic factors
Obesity
Malignancy
Immobilization
Dehydration
Peroral Contraceptives
Hormone Replacement Therapy
Pregnancy and postpartum
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2. Pulmonary embolism
Thrombophilia
= inherited/ acquired defects of haemostasis leading to a predisposition to arterial or venous thrombosis
Thrombosis
1. Arterial
• association of atheroma plaque -> rupture -> platelets adhere to damaged vessel- “white
thrombus” formation-> embolization+/- obstruction
• Risk factors related= same as to atherosclerosis
• occurs in areas of turbulent flows- bifurcations of arteries
- in the heart (prosthetic valves, left ventricle -after myocardial infarction, left atrium- mitral
valve disease)
2. Venous (ad pulmonary embolism)
(a) Definition and etiology of pulmonary embolism
Pulmonary embolism (PE) is the obstruction of one or more pulmonary arteries by solid, liquid, or gaseous
masses. In most cases, the embolism is caused by blood thrombi, which arise from the deep vein system in
the legs or pelvis (deep vein thrombosis- DVT) and embolize to the lungs via the inferior vena cava. This
condition causes a redistribution of blood in the lungs, which impairs ventilation-perfusion matching (V/Q
mismatch) and gas exchange. There are both respiratory (increased dead space, hypoxemia,
hyperventilation) and hemodynamic consequences (increased pulmonary vascular resistance, increased
right ventricular afterload) from PE. In addition, the humoral and reflex mechanisms contribute to pulmonary
arterial constriction.
Types of emboli:
• thromboembolism
• septic embolism
• venous air embolism
• fat embolism
• amniotic fluid embolism
• tumour embolism
• foreign material embolism (e.g., silicone, broken catheters, guide wires, vena cava filters,
embolization coils, and endovascular stent components)
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Acute and Subacute vs. Chronic
PE can be characterized as acute or chronic. PE is pathologically characterized as acute when the embolus
is situated centrally within the vascular lumen or if it occludes the vessel, usually causing distension of the
vessel. An embolus is chronic if it is eccentric and contiguous with the vessel wall, it reduces the diameter
by more than 50%, and there is evidence of recanalization within the thrombus.
Hemodynamically stable vs. unstable PE
Hemodynamically unstable PE is also called "massive" or "high-risk" PE. It is that which results in
hypotension and/or persistent tachycardia (heart rate over 100 beats per minute with signs or symptoms of
shock). Hypotension is defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure
of ≥40 mmHg from baseline for a period >15 minutes or hypotension that requires vasopressors or inotropic
support and is not explained by other causes such as sepsis, arrhythmia, left ventricular dysfunction from
acute myocardial ischemia or infarction, or hypovolemia. Although hemodynamically unstable PE is often
caused by large (ie, massive) PE, it can sometimes be due to small PE in patients with underlying
cardiopulmonary disease. Thus, the term "massive" PE does not necessarily describe the size of the PE as
much as its hemodynamic effect. Patients with hemodynamic instability due to PE are at risk of obstructive
shock.
Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable
PE. There is a spectrum of severity within this population ranging from patients who present with small, mildly
symptomatic or asymptomatic PE (also known as "low-risk PE") to those who present with mild or borderline
hypotension that stabilizes in response to fluid therapy, or those who present with right ventricle dysfunction
(also known as "submassive" or "intermediate-risk" PE).
Symptomatic vs. Asymptomatic
Asymptomatic PE refers to finding PE on imaging, without the patient having any clinical symptoms.
(b) Epidemiology, risk factors and clinical presentation
The overall incidence is higher in males compared with females (56 versus 48 per 100,000, respectively).
The incidence rises with increased age, especially in women (NÆSS 2007).
Special population:
• Pt. with malignancy- tumour type, location, stage, and time since diagnosis influence VTE risk, in
general, 10x higher than the normal population
• Pt. with stroke- deep vein thrombosis (DVT) is common (up to 10 % pt. after stroke)
• Pregnancy
Venous thromboembolism (VTE) is approximately 10 times more common in the pregnant population
(compared with non-pregnant women) with an incidence of 1 in 1000 and the highest risk in the postnatal
period. Most women with pregnancy-associated VTE will have identifiable risk factors (obesity, age >35
years old, Parity ≥3, smoking, varicose veins, previous pregnancy-related VTE, etc.) All three components
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of “Virchow’s triad” of venous stasis, hypercoagulability and vascular damage occur in the course of
pregnancy and delivery. The majority of gestational deep vein thrombosis are ileofemoral- often nondetectable
by USG, in contrast to those who are not pregnant, in whom the majority are popliteofemoral.
Risk factor Example
Circulation Stasis Immobility
Prolonged travel
Recent surgery
Congestive heart failure
Obesity
Hypercoagulability Pregnancy
Medication (hormonal contraceptives, hormone replacement therapy,
antipsychotics, fibrates...)
Severe burns
Malignancy (solid tumours, leukaemias, lymphomas)
Acute medical illness (e.g., AIDS, SLE, Ulcerative colitis)
Hereditary factors (e.g protein C/S deficiency, factor V Leiden)
Endothelial damage Fracture
Previous DVT
Trauma
Other Smoking, Haemolytic anaemias, inflammatory bowel disease...
Table 2: Risk factors of Virchow Triad
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Classic Risk Factors for PE: “THROMBOSIS”
Trauma/Travel
Hypercoagulable state/Hormone Replace Therapy
Recreational drugs (IVDU)
Older
Malignancy
Birth Control
Obesity/Obstetrical
Surgery
Immobilization
Smoking
Clinical presentation
Various (asymptomatic-> cardiac shock), non-specific
• abrupt onset of chest pain
• shortness of breath, dyspnea, cough
• hypoxia, tachypnea
• fever (if pulmonary infarct)
• syncope
• hemoptysis
• Deep vein thrombosis (erythematous,
swollen, warm lower extremity)
Table 3: Symptoms of PE
(c) Investigation
• clinical assessment of the likelihood of PE
Wells's score should be estimated. The Wells criteria were applied and the score was calculated to
determine the probability of PE into a three-level system of:
- Low (score <2)
- Intermediate(score 2 - 6)
- High (score >6)
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Table 4: Wells score
A low-risk patient (< 2 points) can be worked up with a D-dimer. An intermediate-risk patient (2-6 points) can
be worked up with a D-dimer or CT angiogram pending clinical suspicion. A high-risk patient (score > 6
points) should be worked up with a CT angiogram. The only exception to this rule is in very high-risk patients
with a classic presentation for PE who have unstable vitals. In these patients, it is appropriate to first treat
with heparin while a CT angiogram is being ordered/performed to confirm the diagnosis.
D-dimer — D-dimer is one of the fibrin degradation products (FDP), produced when a blood clot gets
dissolved in the body by enzyme plasmin, the level of D-dimer in the blood can rise when there is significant
formation and breakdown of fibrin clots in the body
An elevated D-dimer alone is insufficient to make a diagnosis of PE but can be used to rule out PE with high
certainty (negative predictive value). D-dimer testing is best used in conjunction with clinical probability
assessment.
For patients in whom the risk of PE is thought to be low, a normal D-dimer (<500 ng/mL) effectively excludes
PE, and typically no further testing is required.
In contrast, an elevated D-dimer (>500 ng/mL) should prompt further testing with diagnostic imaging.
For patients in whom the risk of PE is thought to be high, a normal D-dimer is not as helpful for excluding
the diagnosis. These patients should undergo diagnostic imaging, preferably with CTPA.
Use D-dimers wisely:
• test low-risk patients
• test when you expect it will be negative (to rule out PE)
• don’t test D-dimer if you plan to order a CT regardless
• D-dimers in pregnancy rise in the 2nd and 3rd trimester, and stay high post-partum, are not
recommended investigation of suspected acute VTE in pregnancy
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(d) Imagining
Chest CT with angiography (CTPA)
• A CT scan uses X-rays to build cross-sectional images ("slices") of the
body
• cross-sectional images are constructed from measurements of attenuation
coefficients of x-ray beams passing through the object studied
• angiography- to check for narrowed or blocked arteries in various vessels of the heart, the aorta and
other large blood vessels, the lungs, the kidneys, the head and neck by using contrast
• test of choice in most circumstances, “golden standard”
• suitable for massive or submassive PE
• allows adequate visualization of the pulmonary arteries down to at least the segmental level, but cannot
rule out subsegmental PE
• be cautious in cases where CTPA results are discordant and clinical judgement
• positive CTPA showing a filling defect confirms the diagnosis of PE
Perfusion scan
• ↓ pulmonary perfusion without decreased ventilation to a given
area (V/Q mismatch)
• reserved for patients in whom the CTPA is contraindicated (eg,
history of moderate or severe contrast allergy, renal failure,
hypotension, advanced heart failure, or inability to tolerate CT
scanning due to morbid obesity, pregnancy or when CTCA is
inconclusive)
• hemodynamically stable patient and chronic thromboembolic state
• i.v injection of technetium-labelled particles, these block a small fraction of the pulmonary capillaries and
thereby enable scintigraphic assessment of lung perfusion (gamma camera)
• risk of further occlusion of pulmonary vessels is only theoretical as the number of capillaries (approx.
300 million) far outnumbers the number of particles injected (usu. 200, 000-500 000) so there is a wide
safety margin
• normal chest Xray is useful- then only a perfusion scan is performed
• high frequency of non-diagnostic tests
Echocardiography
• Ultrasonography is a technique that uses high-frequency sound waves (1-20 MHz) produced and
received by the probes), ultrasound wave is produced by a probe using the piezoelectric effect
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• Higher frequency means greater resolution but decreases penetration
• bedside investigation
• presence of a clot in the right heart or new right heart strain
• useful for prognostic purposes in patients with confirmed PE
• PE increases the pulmonary artery pressure, which increases right ventricular after-load, resulting in:
✓ Right ventricular dilatation
✓ Hypokineses
✓ Tricuspid valve regurgitation
✓ Ultimately, right ventricular failure
An echocardiogram of a patient with a massive pulmonary
embolus. Transthoracic echocardiogram (parasternal view)
showing the aorta (Ao), left atrium (LA), a dilated right ventricle
(RV) and displacement of the intra-ventricular septum (IVS) into
the left ventricle (LV) in a patient with a massive pulmonary
embolus
Lower-extremity ultrasound with Doppler
• when neither CTCA nor V/Q scan can be performed or are
inconclusive
• evaluate for coexisting DVT
• validated criteria for deep vein thrombosis (DVT)- incomplete
collapsibility of the vein
Catheter-based pulmonary angiography
• historically gold-standard confirmatory test
• rarely used, less invasive options available
• contrast is injected under fluoroscopy via a femoral vein catheter introduced into the right atrium and
ventricle into the pulmonary outflow tract and then advanced further into each of the main pulmonary
arteries
• a bolus of contrast is injected to outline the pulmonary vascular tree
• the disadvantage of this procedure: local bleeding complications, haematoma or pseudoaneurysm
in the groin and the general risk (small but definite) of cardiac arrhythmia
• used to guide percutaneous catheter-directed treatment of PE
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• diagnosis of PE based on direct evidence of thrombi in 2 projections or defect in the filling of the
pulmonary artery branch
Magnetic resonance pulmonary angiography (MRPA)
• imaging option for diagnosis of PE in patients in whom neither CTPA nor V/Q scan can be performed
• a high proportion of inconclusive scans
• no ionising radiation is involved
Other:
ECG
• visual display of the electrical activity of the heart
• 3 or 12 leads
• to rule out other diagnoses or for stratification of risk
• right ventricle pressure overload and dysfunction
• in hemodynamically unstable patient absence of echocardiographic signs of right ventricle overload or
dysfunction practically exclude PE as a cause of hemodynamic instability
• most commonly nonspecific ST and T-wave changes, tachycardia
Findings that correlate with cor pulmonale acutum
• sinus tachycardia
• incomplete RBBB
• flipped T waves in the anterior leads
• S1Q3T3- deep S wave in lead I, Q wave in III, inverted T wave in III (poor sensitivity & specificity)
• Right ventricular strain pattern – T wave inversions in the right precordial leads (V1-4) ± the inferior leads
(II, III, aVF). This pattern is associated with high pulmonary artery pressures (34%)
• Dominant R wave in V1 – a manifestation of acute right ventricular dilatation
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• Right atrial enlargement (P pulmonale) – peaked P wave in lead II > 2.5 mm in height
I aVR V1 V4
II aVL V2 V5
II aVF V3 V6
inferior anterior lateral
Arterial blood gas analysis
• typically shows evidence of respiratory alkalosis with low partial oxygen pressure, low partial carbon
dioxide pressure, and elevated pH
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The diagnosis of PE is based primarily on clinical findings and is confirmed by the detection of an embolism
in contrast to CT pulmonary angiography (CTPA). Staffing burdens for specific tests (e.g., V/Q scanning
and vascular studies of the lower extremities) may impede the clinician's ability to make a timely diagnosis.
Table 6: PE guideline algorithm
(e) Management
Asses hemodynamic stability:
a) hemodynamically stable
• ABCD approach
• oxygen if needed
• empiric initial anticoagulation (0-10 days) depending upon the clinical suspicion for PE, risk of bleeding,
and expected timing of definitive diagnostic tests
• for those who have contraindications to anticoagulation or have an unacceptably high bleeding risk,
placement of an inferior vena cava (IVC) filter should be performed
b) hemodynamically unstable ABCD
• oxygenation and stabilizing the airway with intubation and mechanical ventilation, if necessary
• restoring perfusion with intravenous fluid resuscitation and vasopressor support
• immediate anticoagulation with unfractionated heparin
• patient in cardiogenic shock due to PE is managed with thrombolytic therapy (alteplase)
• prompt imaging for definitive diagnosis (usually CTPA) when pt. is stabilized
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Once the diagnosis is made the patient should be started on anticoagulation therapy:
Empiric anticoagulation with heparin is initiated to prevent further thromboembolisms as well as to promote
the gradual dissolution of the embolism and the underlying thrombosis.
Options for initial anticoagulation include the following:
• subcutaneous LMWH or fondaparinux (once daily injections; heparin-induced thrombocytopenia
[HIT])
• non-vitamin K antagonist oral (NOACs)
Rivaroxaban is the only direct oral anticoagulant for monotherapy (i.e., no pre-treatment with heparin
necessary)
OR
• intravenous unfractionated heparin (UFH) - patients with severe renal failure, for patients in whom
there is a high likelihood that acute reversal of anticoagulation will be needed (e.g., procedure or at
increased risk of bleeding) as well as those with hemodynamic instability
Non-vitamin K antagonist oral anticoagulants are not suitable for the treatment of hemodynamically unstable
PE or massive iliofemoral DVT. In fulminant PE with shock, resolution of the thrombus with thrombolytic
agents or removal in emergency surgery is attempted.
Catheter-directed thrombus removal with or without thrombolysis/ surgical embolectomy:
• hemodynamically unstable PE in whom thrombolytic therapy is contraindicated, fail thrombolysis
• anticoagulant therapy is generally discontinued during the thrombolytic infusion
Definite therapy – oral anticoagulants
• long-term anticoagulant therapy is administered beyond the initial few days of anticoagulation for a
finite period of typically three to six months, and up to 12 months
Target INR
1,5 Pulmonary embolism, proximal and calf deep vein thrombosis, recurrence of venous
thromboembolism where no longer on warfarin therapy, symptomatic inherited thrombophilia, atrial
fibrillation, cardioversion, mural thrombus, cardiomyopathy
3,5 Recurrence of venous thromboembolism while on warfarin therapy, antiphospholipid syndrome,
mechanical prosthetic heart valve, coronary artery graft thrombosis
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(f) Monitoring and follow up
Therapeutic levels of anticoagulation in patients receiving heparin, warfarin, NOACs –
• Warfarin: increased PT/INR, no change to PTT or TT (routinely monitored)
• Unfractionated heparin a PTT (prolonged) (routinely monitored)
• Direct thrombin inhibitors: prolonged TT, no change to PTT or PT (not routinely monitored)
• Direct factor Xa inhibitors: prolonged PT and PTT, unchanged TT (not routinely monitored)
• development of conditions that affect the half-life of the anticoagulant used (eg, renal failure,
pregnancy, weight gain/loss, drug interactions) should also be followed
Complications
• Early complication: recurrence (usually 1 to 2 weeks after initial diagnosis)
• Pulmonary infarction -most cases do not result in infarction due to a large degree of collateral
circulation in the lungs, occurs when a patient has a reduction in pulmonary blood flow secondary to
decreased cardiac output or obstructive lung disease
• Complications of the therapy itself including bleeding
• Death- due to right ventricular failure, obstructive shock
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Sensitivity and specificity, positive and negative predicting value in clinical tests
Sensitivity= true positives/ (true positives+ false negative)
• measures how often the clinical test correctly identifies the sick patients with the disease
(also known as the “true positive” rate)
• highly sensitive test flags almost everyone who has the disease and does not generate many falsenegative
results
• example: a test with 90% sensitivity will correctly return a positive result for 90% of people who have
the disease, but will return a negative result — a false-negative — for 10% of the people who have
the disease and should have tested positive
Specificity= true negatives/(true negatives+ false positives)
• measures the test's ability to correctly generate a negative result for people who don’t have the
condition that’s being tested for (also known as the “true negative” rate)
• test with high specificity correctly rules out almost everyone who doesn't have the disease and won't
generate many false-positive results
• example: a test with 90% specificity will correctly return a negative result for 90% of people who
don’t have the disease, but will return a positive result — a false-positive — for 10% of the people
who don’t have the disease and should have tested negative
Positive predicting value = True positives/(true positives + false positives)
• precision rate and measures the proportion of patients who are correctly diagnosed when they test
positive
Negative predicting value= True negatives/(true negatives+ false negatives)
• measures the proportion of patients with negative tests being truly disease free
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Resources
• https://e-coretvasa.cz/pdfs/cor/2020/02/03.pdf
• NÆSS, I.A., CHRISTIANSEN, S.C., ROMUNDSTAD, P., CANNEGIETER, S.C., ROSENDAAL,
F.R. and HAMMERSTRØM, J. (2007), Incidence and mortality of venous thrombosis: a population‐
based study. Journal of Thrombosis and Haemostasis, 5: 692-699. doi:10.1111/j.1538-
7836.2007.02450.x
• Amboss [online]. [cit. 2019-10-22]. Dostupné z:
https://www.amboss.com/us/knowledge/Pulmonary_embolism
• Amboss [online]. [cit. 2020-02-02]. Dostupné z:
https://www.amboss.com/us/knowledge/Oral_anticoagulants
• Medscape eMedicine [online]. [cit. 2019-10-22]. Dostupné z: ttps://emedicine.medscape.com/
• Uptodate [online]. [cit. 2019-10-22]. Dostupné z: https://www.uptodate.com
• S.ALPER, Brian S. Alper a Cynthia Brown. Pisa model accurately predicts the probability of
pulmonary embolism. Clinicaladvisor.com [online]. 6.11.2008 [cit. 2020-01-27]. Dostupné z:
https://www.clinicaladvisor.com/home/evidence-based-medicine/pisa-model-accurately-predicts-
probability-of-pulmonary-embolism/
• Lab Tests Online: Your trusted Guide [online]. [cit. 2020-02-02]. Dostupné z:
https://labtestsonline.org/tests/d-dimer
• https://medschool.co/tests/abg
• https://www.csarim.cz/content/uploads/2018/11/rotem-pro-zacatecniky.pdf
• https://emergencymedicinecases.com/episode-21-respiratory-emergencies-1-pulmonary-
embolism/
• https://academic.oup.com/eurheartj/article/35/43/3033/503581#133919899
• https://litfl.com/ecg-changes-in-pulmonary-embolism/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818214/