THROMBOSIS AND BLEEDING - SE ÁOK I. sz. Belgyógyászati ... · Thrombosis and bleeding,...
Transcript of THROMBOSIS AND BLEEDING - SE ÁOK I. sz. Belgyógyászati ... · Thrombosis and bleeding,...
Thrombosis and bleeding, Semmelweis University, september, 2011
THROMBOSIS
AND
BLEEDING
Klara Gadó MD. PhD.
Senior Professor of Internal Medicine
Semmelweis University,
Budapest
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).
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
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.
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
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
Thrombosis and bleeding, Semmelweis University, september, 2011
Clinical assessment
of VTE(venous thromboembolism)
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
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%
Thrombosis and bleeding, Semmelweis University, september, 2011
Examination of Homans’ sign
• How to perform?
• Flex knee slightly; Dorsiflex foot
Thrombosis and bleeding, Semmelweis University, september, 2011
But !
• In the 50 % of cases
people with DVT
do not get any symptoms!!!!!
Thrombosis and bleeding, Semmelweis University, september, 2011
Diagnosis of DVT
• ultrasound
Cross sectionLongitudinal section
Thrombosis and bleeding, Semmelweis University, september, 2011
Diagnostics
• DVT in the lower limb, color Doppler,
Thrombosis and bleeding, Semmelweis University, september, 2011
Pulmonary embolism
• about 30,000 people die each year in the United
States
• Often post-mortem diagnosis
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
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)
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.
Thrombosis and bleeding, Semmelweis University, september, 2011
Pulmonary embolism
• COMPUTED TOMOGRAPHY (CT) SCAN,
• MAGNETIC RESONANCE IMAGING
(MRI),
• pulmonary angiography,
• ventilation/perfusion scan
• echocardiography.
Thrombosis and bleeding, Semmelweis University, september, 2011
CT image of pulmonary embolism
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.
Thrombosis and bleeding, Semmelweis University, september, 2011
Laboratory findings
• D-dimer test
• Bedside test
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
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)
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
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.
Thrombosis and bleeding, Semmelweis University, september, 2011
Risk factors of thrombosis
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
Thrombosis and bleeding, Semmelweis University, september, 2011
Aquired risk factors
• Persistant
• Advancing age
• Malignancy
• Antiphosphilipid antibodies
• Prior history of VTE/PE
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)
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
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
Thrombosis and bleeding, Semmelweis University, september, 2011
MODERN TREATMENT
OF VTE
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
Thrombosis and bleeding, Semmelweis University, september, 2011
IN CASE OF
RENAL INSUFFICIENCY
• need for decreasing heparine dose
• practical to give UFH
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
Thrombosis and bleeding, Semmelweis University, september, 2011
THE SIDE-EFFECTS OF HEPARIN I.
• HEPARIN-INDUCED
THROMBOCYTOPENIA (HIT)
• OSTEOPOROSIS
• ALOPECIA
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
Thrombosis and bleeding, Semmelweis University, september, 2011
•self-injection
•neat therapy skilling of patients
LMWH
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)
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
Thrombosis and bleeding, Semmelweis University, september, 2011
Bleeding disorders
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
Thrombosis and bleeding, Semmelweis University, september, 2011
Congenital Bleeding disorders
Coagulation factor deficiency
• Hemophilia A (fVIII)
• Hemophilia B (fIX)
• Von Willebrand’s disease
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).
Thrombosis and bleeding, Semmelweis University, september, 2011
Genetic aspects
• The gene for factor VIII is located
on the long arm of chromosome X.
Thrombosis and bleeding, Semmelweis University, september, 2011
„King’s disease”
Queen Victoria
The Tsarevich Alexis had suffered from hemophilia,
Thrombosis and bleeding, Semmelweis University, september, 2011
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,
Thrombosis and bleeding, Semmelweis University, september, 2011
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.
Thrombosis and bleeding, Semmelweis University, september, 2011
Amniocentesis
• Usually performed 14-20 weeks
• Risk of fetal death estimated as 1:200
Thrombosis and bleeding, Semmelweis University, september, 2011
Laboratory findings
• Prolonged PTT
• Normal PT
• Normal bleeding time
• Normal platelet count
Thrombosis and bleeding, Semmelweis University, september, 2011
Factor levels
• Factor activity
– Mild 5-25%
– Moderate 2-5%
– Severe 1%
• PTT prolonged only if activity 25%
• Spontaneous bleeding: 5%
Thrombosis and bleeding, Semmelweis University, september, 2011
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%.
Thrombosis and bleeding, Semmelweis University, september, 2011
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.
Thrombosis and bleeding, Semmelweis University, september, 2011
• Subcutaneous hematoma
Epidural hematoma
gingival bleeding
Thrombosis and bleeding, Semmelweis University, september, 2011
• Joint deformity
Thrombosis and bleeding, Semmelweis University, september, 2011
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
Thrombosis and bleeding, Semmelweis University, september, 2011
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
Thrombosis and bleeding, Semmelweis University, september, 2011
Therapy of the future: gene therapy
• Genes of clotting factors are taking into liver cells
Thrombosis and bleeding, Semmelweis University, september, 2011
Von Willebrand disease
• vWf is a large multimeric molecule
• Role:
– protecting fVIII
– Platelet binding to endothel
Thrombosis and bleeding, Semmelweis University, september, 2011
Classification
1. vWf protein
2. Inappropriate vWf function
3. No vWf : severe bleeding
Thrombosis and bleeding, Semmelweis University, september, 2011
Clinical signs
• Bleeding during surgery
• Postoperative re-bleeding
Thrombosis and bleeding, Semmelweis University, september, 2011
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
Thrombosis and bleeding, Semmelweis University, september, 2011
therapy
• Desmopressin (DDAVP),
• VIIIf concentrate
• cryoprecipitate
• antifibrinolytics
• platelet
Thrombosis and bleeding, Semmelweis University, september, 2011
Aquired
coagulopathies
Thrombosis and bleeding, Semmelweis University, september, 2011
Aquired coagulopathies
• More frequent
• Vitamin K dependent coagulation factor
deficiency
– Liver disease
– malabsorption
• Disseminated intravascular coagulation
Thrombosis and bleeding, Semmelweis University, september, 2011
Liver disease
• Vitamin K dependent coagulation factor deficiency
• AT III , vWf
• aPTT, PT
• Liver biopsy is dangerous
• Platelet count
Thrombosis and bleeding, Semmelweis University, september, 2011
THANK YOUFOR
YOUR ATTENTION