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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

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