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Thrombosis and bleeding, Semmelweis University, september, 2011
THROMBOSIS
AND
BLEEDING
Klara Gadó MD. PhD.
Senior Professor of Internal Medicine
Semmelweis University,
Budapest
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Thrombosis and bleeding, Semmelweis University, september, 2011
• formation of a blood clot in a blood vessel
• Blood can not flow
• Organ supply is
not appropriate,
• Organ damage, necrosis
What is thrombosis?
Blood clot.
Coloured scanning electron micrograph (SEM)
The red blood cells (erythrocytes, red) are trapped in filaments of fibrin protein (grey).
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Thrombosis and bleeding, Semmelweis University, september, 2011
• Clot forms when
• circulation to a particular part of the body is abnormally sluggish
• damage has been done to a blood vessel,
• there is an imbalance between clotting and bleeding factors.
bleeding thrombosis
Conditinons promoting clot formation
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Thrombosis and bleeding, Semmelweis University, september, 2011
How common is DVT?
• every year about 1 in 5,000 people are diagnosed
with DVT.
• The risk is even greater among older people.
• affects approximately 200,000 Americans
per year
•
•Source:Fowkes FJI, Price JF, Fowkes FGR, et al.European Journal of Vascular and Endovascular Surgery. 2003; 25: 1-5.
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Thrombosis and bleeding, Semmelweis University, september, 2011
What are the consequences of DVT?
• Leg ulcer
• is an extremely common problem affecting
about 1-2% of the general population in the UK.
• Postthrombotic syndrome
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Thrombosis and bleeding, Semmelweis University, september, 2011
What are the consequences of DVT?
• if the clot breaks free and travels
through the veins where it can
reach the lungs,
obstructing the pulmonary artery
or its branches, which supply the
lungs with blood
• This is pulmonary embolism
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Thrombosis and bleeding, Semmelweis University, september, 2011
Clinical assessment
of VTE(venous thromboembolism)
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Thrombosis and bleeding, Semmelweis University, september, 2011
Symptoms of
deep vein thrombosis
in the lower leg
• swelling
• erythemia (redness)
• warmth in the area
caused by capillary
congestion.
• Pain
• stiff and shiny skin
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Thrombosis and bleeding, Semmelweis University, september, 2011
Signs of deep vein thrombosis
in the lower leg
• Physical examination: Homans’ sign:
development of pain in the calf or popliteal region
on forceful dorsiflexion of the ankle
with the knee in flexed position.
• sensitivity 13 to 48%
• specificity from 39 to 84%
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Thrombosis and bleeding, Semmelweis University, september, 2011
Examination of Homans’ sign
• How to perform?
• Flex knee slightly; Dorsiflex foot
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Thrombosis and bleeding, Semmelweis University, september, 2011
But !
• In the 50 % of cases
people with DVT
do not get any symptoms!!!!!
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Thrombosis and bleeding, Semmelweis University, september, 2011
Diagnosis of DVT
• ultrasound
Cross sectionLongitudinal section
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Thrombosis and bleeding, Semmelweis University, september, 2011
Diagnostics
• DVT in the lower limb, color Doppler,
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Thrombosis and bleeding, Semmelweis University, september, 2011
Pulmonary embolism
• about 30,000 people die each year in the United
States
• Often post-mortem diagnosis
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Thrombosis and bleeding, Semmelweis University, september, 2011
Pulmonary embolism
• incidence of the disease:
50-150/100 000 inhabitant/year
• 10 % of cases leading to
immediate death
• mortality among survivors: 30 %
• with proper treatment this can be
lowered to 10 %
• Dg: spiral CT, echocardiography
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Thrombosis and bleeding, Semmelweis University, september, 2011
Symptoms of pulmonary embolism
• sudden, severe CHEST PAIN
• DYSPNEA (difficulty BREATHING)
• diaphoresis (breaking into a cold sweat)
• HYPOTENSION (low BLOOD PRESSURE)
• TACHYCARDIA (rapid heart rate)
• TACHYPNEA (rapid BREATHING)
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Thrombosis and bleeding, Semmelweis University, september, 2011
ECG signs of PE• The most common ECG finding is sinus tachycardia,
• the "S1Q3" pattern of acute cor pulmonale is classic (only occurs in about 10%) A large S wave in lead I, a Q wave in lead III,
• indicates acute right heart strain.
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Thrombosis and bleeding, Semmelweis University, september, 2011
Pulmonary embolism
• COMPUTED TOMOGRAPHY (CT) SCAN,
• MAGNETIC RESONANCE IMAGING
(MRI),
• pulmonary angiography,
• ventilation/perfusion scan
• echocardiography.
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Thrombosis and bleeding, Semmelweis University, september, 2011
CT image of pulmonary embolism
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Thrombosis and bleeding, Semmelweis University, september, 2011
Ventillation/perfusion scan image of
pulmonary embolism• Lung scintigraphy is an
indirect imaging method which non-invasively visualizes the perfusion defect caused by an embolus
• the procedure is highly sensitive and easily detects even small embolisms on a subsegmental level.
• coupled with a ventilation scan specificity improves
• a typical mismatch defect caused by pulmonary embolism.
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Thrombosis and bleeding, Semmelweis University, september, 2011
Laboratory findings
• D-dimer test
• Bedside test
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Thrombosis and bleeding, Semmelweis University, september, 2011
D-dimer test
• D-dimers are specific cross-linked fibrin derivatives
product of plasmin-mediated fibrinolytic degradation.
marker of fibrinolytic activity.
• The D-dimer assay can be used as a “rule out” test
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Thrombosis and bleeding, Semmelweis University, september, 2011
Non-pathological conditions associated
with elevated D-dimer titres include:
• Age (healthy elderly people)
• Cigarette smoking
• Functional impairment
• Post-operatively
• Pregnancy
• Race (e.g. African Americans)
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Thrombosis and bleeding, Semmelweis University, september, 2011
Pathological conditions associated
with elevated D-dimer titres include• Acute coronary syndromes
• Acute upper gastrointestinal haemorrhage
• Aortic dissection
• Arterial or venous thromboembolism
• Atrial fibrillation
• Consumptive coagulopathy – DIC
• Infection
• Malignancy
• Pre-eclampsia
• Stroke
• Superficial thrombophlebitis
• Trauma
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Thrombosis and bleeding, Semmelweis University, september, 2011
D-dimer & VTE
• The D-dimer test is a marker of blood
clotting activity and is not diagnostic of
VTE.
• When used appropriately the D-dimer test
helps “rule out” VTE if the test is negative
and the chance of the patient having a VTE
is relatively low.
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Thrombosis and bleeding, Semmelweis University, september, 2011
Risk factors of thrombosis
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Thrombosis and bleeding, Semmelweis University, september, 2011
Risk factors
• Thrombophilia
a group of abnormalities where there is a
tendency for the occurrence of thrombosis,
• may be classified as
inherited or
acquired
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Thrombosis and bleeding, Semmelweis University, september, 2011
Aquired risk factors
• Persistant
• Advancing age
• Malignancy
• Antiphosphilipid antibodies
• Prior history of VTE/PE
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Thrombosis and bleeding, Semmelweis University, september, 2011
Aquired risk factors
• Transient• Recent surgery
• Recent trauma
• Pregnancy, labour
• Prolonged immobilization(bedrest, travelling, leg fracture)
• Comorbities(heart failure, nephrotic syndrome)
• Drugs(oral contraceptives, chemotherapyhormon replacement therapy)
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Thrombosis and bleeding, Semmelweis University, september, 2011
Inherited risk factors
• Antithrombin deficiency
• Protein C and S deficiency
• Factor V Leiden mutation
• Factor II G20201A gene mutation
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POSSIBLE INDICATORS
OF THROMBOPHILIA
• Thrombosis at early age (under 50)
• Thrombosis at unusual sites
• Thrombosis recurrence
• Thrombosis developed by mild provoking
factor
• Habitual abortion, miscarriage, still-birth
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Thrombosis and bleeding, Semmelweis University, september, 2011
MODERN TREATMENT
OF VTE
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Thrombosis and bleeding, Semmelweis University, september, 2011
Post-surgical
TROMBOPROFILAXIS
• No thrombocyte aggregation inhibitor
1 week before surgery
• Changing vitamin K antagonist to LMWH
• Na-heparin 12 hours before operation
• EDA10-12 hours after LMWH
LMWH can be given 4 hours after intervention
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Thrombosis and bleeding, Semmelweis University, september, 2011
IN CASE OF
RENAL INSUFFICIENCY
• need for decreasing heparine dose
• practical to give UFH
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Thrombosis and bleeding, Semmelweis University, september, 2011
Monitoring of the treatment
• Vitamin K antagonist:
• Measuring INR
• Monitoring heparin therapy:
• Measuring aPTT
• Monitoring LMWH efficiency:
• anti-Xa activity
• Obes patients
• on pregnant women
• Renal impairment
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Thrombosis and bleeding, Semmelweis University, september, 2011
THE SIDE-EFFECTS OF HEPARIN I.
• HEPARIN-INDUCED
THROMBOCYTOPENIA (HIT)
• OSTEOPOROSIS
• ALOPECIA
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Thrombosis and bleeding, Semmelweis University, september, 2011
THE SIDE-EFFECTS OF HEPARIN
II.
•HIT
• 5 days after the beginning of the therapy
• thrombocytopenia + thrombosis
• Therapy:
• thrombocyte prohibited
give direct thrombin inhibitors (lepirudin)
• Monitoring the number of thrombocytes
during the therapy
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Thrombosis and bleeding, Semmelweis University, september, 2011
•self-injection
•neat therapy skilling of patients
LMWH
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Thrombosis and bleeding, Semmelweis University, september, 2011
Coumarin (warfarin, Syncumar)
• Some aspects:•narrow therapy range
•Strong plasma protein binding
• Appropriate dose• Starting with a small dose• Starting: always overlapping with heparin• Frequent control measuring INR• Education (diet, medicines)
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Thrombosis and bleeding, Semmelweis University, september, 2011
•In the beginning of the therapy
•More frequent with Protein C absence
•Histology:
fibrinoid thrombus in small veins
•Profilaxis:
low starting dose, heparin protection
COUMARIN NECROSIS
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Thrombosis and bleeding, Semmelweis University, september, 2011
Bleeding disorders
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Thrombosis and bleeding, Semmelweis University, september, 2011
Classification of bleeding disorders
• Congenital
• Coagulation factor deficiency
• Aquired
• Consumption– DIC
• Abnormal synthesis of coagulation factors– Liver diseases
• Iatrogenic
• Overdosing anticoagulants
• Antibodies against coagulation factors
• toxic
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Thrombosis and bleeding, Semmelweis University, september, 2011
Congenital Bleeding disorders
Coagulation factor deficiency
• Hemophilia A (fVIII)
• Hemophilia B (fIX)
• Von Willebrand’s disease
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Thrombosis and bleeding, Semmelweis University, september, 2011
Hemophilia A
• Incidence: 1:10.000
• Factor VIII is synthesized by the liver.
• It circulates in plasma in a form bound to a
transport protein known as
Von Willebrand factor (VWF).
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Genetic aspects
• The gene for factor VIII is located
on the long arm of chromosome X.
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„King’s disease”
Queen Victoria
The Tsarevich Alexis had suffered from hemophilia,
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Clinical aspects
• Severe hemophilia A : in 30 to 40% of cases.
• The most common hemorrhagic episodes consist of:
• hemarthrosis: 70%, (joint deformity)
• subcutaneous or intramuscular hematomas: 10 to 20%,
• bleeding in the urinary tract, nasal and gastrointestinal
mucosa, and intra-abdominal organs: 10 to 20%.
• Gastrointestinal and central nervous system hemorrhagic
accidents are potentially life-threatening,
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Screening for mutations
• Numerous mutations responsible for
hemophilia A have been described
• screening techniques to characterize patients,
carriers
make prenatal diagnosis
• 1/3 of patients de novo mutation
in a family hitherto unaffected by the disease.
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Amniocentesis
• Usually performed 14-20 weeks
• Risk of fetal death estimated as 1:200
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Laboratory findings
• Prolonged PTT
• Normal PT
• Normal bleeding time
• Normal platelet count
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Factor levels
• Factor activity
– Mild 5-25%
– Moderate 2-5%
– Severe 1%
• PTT prolonged only if activity 25%
• Spontaneous bleeding: 5%
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Treatment
• “replacement therapy” — giving or replacing the clotting factor that is too low or missing.
• Concentrates of the clotting factor are infused, or injected, directly into the bloodstream.
• The specific factors used to treat hemophilia are: Factor VIII for hemophilia A – Factor IX for hemophilia B
• The activity level for factor VIII needed to ensure clotting is around 30%.
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Treatment
• Replacement therapy can be used:
– To prevent bleeding (prophylactic or preventive
therapy)
– To stop bleeding when it occurs, on an as-
needed basis (demand therapy)
• The type of treatment you receive depends
on several things, including whether you
have mild, moderate or severe hemophilia.
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• Subcutaneous hematoma
Epidural hematoma
gingival bleeding
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• Joint deformity
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Inhibitors• Antibodies develop against clotting factors
• Examining the presence of inhibitors
– Mixing studies
– Patient : normal plasma mix: 1:1
– If:
– aPTT has normalized means: factor deficiency
– aPTI does not normalized means: inhibitor is present
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HEMOPHILIA B• FIX deficiency, Christmas-disease
• More scarce, incidence 1:50000
• difference:
only with special laboratroy tests
• Coding gene on chromosome X,
near to gene of fVIII,
much smaller gene than gene fVIII
• Treatment:
• IXf concentrate
• Needed scarcer (IXf T1/2 longer)
• Dose calculation
• (wanted % - actual %) x bwkg = Unit
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Therapy of the future: gene therapy
• Genes of clotting factors are taking into liver cells
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Von Willebrand disease
• vWf is a large multimeric molecule
• Role:
– protecting fVIII
– Platelet binding to endothel
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Classification
1. vWf protein
2. Inappropriate vWf function
3. No vWf : severe bleeding
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Clinical signs
• Bleeding during surgery
• Postoperative re-bleeding
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Diagnosis
• Platelet count may be decreased
• Abnormal bleeding time
• fVIII activity decreased
• Ristocetin-induced platelet aggregation decreased
• vWf ag
• vWf activity decreased
• Normal aPTT, PT
• Special tests
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therapy
• Desmopressin (DDAVP),
• VIIIf concentrate
• cryoprecipitate
• antifibrinolytics
• platelet
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Aquired
coagulopathies
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Aquired coagulopathies
• More frequent
• Vitamin K dependent coagulation factor
deficiency
– Liver disease
– malabsorption
• Disseminated intravascular coagulation
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Liver disease
• Vitamin K dependent coagulation factor deficiency
• AT III , vWf
• aPTT, PT
• Liver biopsy is dangerous
• Platelet count
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Thrombosis and bleeding, Semmelweis University, september, 2011
THANK YOUFOR
YOUR ATTENTION