Bleeding

How does bleeding start and stop?

Blood vessel injury

The capillary contracts to help slow the bleeding.

Platelets make a plug to patch the hole.

Clotting factors in plasmawork together to form a clot over the plug.

Prolonged bleeding in Haemophilia

Haemophilia - clotting factor absent or low. This makes it difficult for the blood to form a clot, so bleeding continues longer than usual (not faster).

FVIII deficiency FIX deficiency

Vessel

injury
Platelet
Release rxn
Platelet
Aggregation
Vasoconstriction
Coagulation
Cascade
Stable
Haemostatic Plug

Congenital bleeding disorders

Haemophilia A (Factor VIII Deficiency)
Haemophilia B (Factor IX Deficiency)
Von Willebrand Disease
Factor X Deficiency
Factor XI Deficiency
Congenital thrombocytopenia
Platelet function defect


Thrombocytopenia

Definition

• Mild: 100 to 150
• Moderate: 50 to 100
• Severe: < 50

Pathophysiology

Four Main Categories
• Redistribution
• Hemodilution
• Bone Marrow Dysfunction
• Platelet Destruction/Consumption

Easy, right?

• Bone Marrow Dysfunction
• MDS
• Leukemia
• Paroxysmal Nocturnal Hemoglobinuria
• Infection
• Alcoholism
• Nutritional Deficits
• ITP (decreased BM production and peripheral destruction)
• Malignancy (extension into BM)

Bone Marrow

• Infection
• Viral
• HIV
• ITP-like syndrome or direct megakaryocyte toxicity
• Direct megakaryocyte toxicity
• Hepatitis C, MMR vaccine and EBV
• Bacterial + Parasites
• BM suppression or DIC in sepsis
• H. pylori, leptospirosis, malaria, babesiosis


Destruction/Consumption
• Almost always antibody mediated
•

Immune Thrombocytopenia

• Pathophysiology
• Inciting event causing autoantibody formation
• Malignancy (CLL)
• Rheumatological diseases (SLE, APS, Evan’s)
• Viral/Bacterial infections
• HIV, Hep C, CMV, VZV
• Sometimes H. pylori, Gram - bacteria and LPS
• Molecular mimicry to Gp2b3a receptor on platelets

Immune Thrombocytopenia

• Diagnosis of exclusion!
• Treatment
• Plt < 20 and bleeding?
• Transfuse with IVIG and/or Steroids
• Plt > 30 and no bleeding?
• No need for treatment
• Treatment Regimens
• Utilize steroids first, usually cheaper and faster
• Prednisone 1 mg/kg/day
• IVIG 1 g/kg/day x 2 days
• Rituximab or Splenectomy if not responsive > 6 months


Principal Bleeding Disorders
Haemophilia A (factor VIII deficiency)
Haemophilia B (factor IX deficiency)
von Willebrand Disease (vWD)
Other

Haemophilia

Haemophilia A
VIII deficiency
X-linked, 1/3rd carriers
<50% FVIIIC.
1:20,000 births
Haemophilia B
IX deficiency
X-linked, 1/3rd carriers
<50% FIXC .
1:100,000
These are clinically indistinguishable

Haemophilia

1:10,000 males FVIII > FIX x 6
X-linked recessive -lyonisation- females can be affected.
1/3 no family history / spontaneous mutation in FVIII/FIX genes of mother.
Molecular diagnosis possible > 90%
Carrier status of mother can be accurately predicted


Inheritance

What are the chances a baby will have haemophilia?

Females XX
Males X Y.

The haemophilia gene is carried on the X chromosome

X-LINKED DISORDER

INHERITANCE OF HAEMOPHILIA

Haemophilia
Spectrum of severity is wide - clinical phenotype tends to be similar in all affected members of the same family
When there is no family history, infants with moderate/severe disease usually present:
post-circumcision bleeding
bad “toddler bruising”
soft tissue/muscle or joint bleeds at 6-18 months of age
RARE, intracranial, ilio-psoas, intra-abdominal, haematuria


DISEASE SEVERITY

50-200% 5-50% 2-5% <1%

Mild Moderate Severe

Detection of Haemophilia

Family history
Symptoms
Haemostatic challenges
Surgery
Dental work
Trauma, accidents
Laboratory testing
APTT prolonged in FVIII/FIX deficiency
F VIII, F IX ,vWF

Ankle bleed

Bleeding following a vein puncture using a vacuum system

Haemophilia in pregnancy
Delivery & neonatal period is a high risk time for baby and carrier mother
In 1/3 of cases there is no family history
31% of carriers with +ve family history not aware of their carrier status at delivery*
Knowledge of carrier status has an impact on delivery and management of baby



CLINICAL PRESENTATION

Bleeding has a prediliction for joints, particularly weight bearing.

Haemarthrosis
Also bleed intramuscularly
Bleed post haemostatic challenge – surgery/dental extraction/injury
Intracranial haemorrhage

HAEMOPHILIA - HAEMARTHROSIS

CHRONIC JOINT BLEEDING

Which joint bleeds are most common?

Most common ankles, knees, and elbows – weight bearing joints

Bleeds in other joints can also happen, including the toes, shoulders, and hips.

What happens in a joint bleed?

joint feels tingly and warm.

Swelling, painful and difficult to move.

Long-term effects of Joint bleeds?
Repeated bleeding causes synovium (lining) to swell

The synovium stops producing the slippery, oily fluid that helps the joint move.

Damages the cartilage- joint stiff, painful and unstable.

With time, most of the cartilage breaks down and some bone wears away. The whole process is called haemophilic arthropathy.

What Happens in a Muscle bleed?

During a bleed, the muscle feels STIFF and PAINFUL.

The bleed causes SWELLING that is WARM and PAINFUL to touch.

In some deeper muscles, the swelling may press on nerves or arteries, causing TINGLING and NUMBNESS

muscle SPASM.

Common Muscle Bleeds

Calf, thigh, and upper arm.

Bleeds in the psoas muscle (front of the hip

Can put pressure on nerves and arteries, causing permanent damage. (numbness – classic sign)

Joints above and below the muscle can’t move properly. May bleed more often.

Nerve damage.

Serious or Life-threatening bleeds?

Head injury -

Throat /airway bleeds

Major loss uncommon except after injury or if related to another medical condition.

Other bleeds may be very serious, but usually not life-threatening, eg bleeds into the eyes, spine, and psoas muscle.

Haemophilia

Mild haemophilia ( 5 - 20 %):
bleed only with trauma and surgery.
Severe haemophilia( < 1%) :
Haemarthroses 2-8 times/month.
Muscle bleeds.
Intracerebral bleeding
Prolonged bleeding with trauma and surgery.

Treatment of Bleeds

Bleeds should be treated quickly to recover more fully, quickly and prevent later damage.

If in doubt, treat. Don’t wait!

Treatment of bleeding disorders- general principles

Avoid IM injections
Avoid NSAIDs
Avoid delay in treating the patient. Treat on suspicion of a bleed
Listen to the patient - he has lifelong experience
Record any treatment given including batch numbers to ensure full traceability of factor concentrates
Contact the haematologist on call if in doubt

Evolution of Clotting Factor Therapy

• 1. Fresh whole blood
• 2. Fresh frozen plasma ( FFP )
• 3. Cryoprecipitate ( “CRYO” )
• 4. Factor VIII / IX concentrates
• 5. Ultra high purity plasma derived factor VIII / IX
• concentrates
• 6. Recombinant factor concentrates
•


Factor Concentrates
• CONCENTRATE
• INDICATION
• HALF - LIFE
• Advate Recombinant
• FVIII Deficiency
• 12 Hours
• BeneFIX
• Recombinant
• FIX Deficiency
• 18 Hours
• Novoseven
• Recombinant
• Patients with inhibitors to FVIII or FIX
• +/-2.7 Hours

Role of factor concentrate

Replaces missing factor

Injected IV

Bleeding stops when enough factor reaches the bleeding site

Treat ASAP

Investigation of bleeding disorders

PT, APTT
Von Willebrand Factor
Specific clotting factor assays
Platelet function testing

Von Willebrand Disease

• 1926
• 5yr old girl – died at 13yr during 4th menstrual period
• 4 siblings died from gastrointestinal haemorrhage
• Both parents had significant bleeding history
• VWF – identified 1950s, purified 1972, sequenced 1985


Von Willebrand Disease
Up to 1% of the population
125 / million have a clinically significant bleeding disorder
Autosomal inheritance


















Von Willebrand factor
Large glycoprotein produced by endothelial cells and megakaryocytes
Mediates platelet to endothelial adhesion
Mediates platelet to platelet interaction
Carrier protein for Factor VIII

Von Willebrand Disease

MILD/MODERATE BLEEDING TENDANCY mucocutaneous bleeding
easy bruising
epistaxis
menorrhagia
recurrent iron deficiency
family history

VWD Treatment

Avoid NSAIDs
Avoid IM injections
Vaccinate against Hepatitis A and B
Treat anaemia
Dental hygiene


Very few patients require treatment with clotting factor concentrate

VWD TREATMENT -Specific measures

–plasma derived product

DDAVP

Cyclocapron

DDAVP

Promotes release of VWF and factor VIII from endothelial cells
0.3ug/kg in 100mls N/Saline over 30 mins
Average response is a threefold rise in VWF and FVIII
Treatment of choice in responsive patients for spontaneous bleeding , trauma or minor surgery
Intra nasal DDAVP

VWD TREATMENT -Specific measures

Cyclocapron
Antifibrinolytic agent
Stabilises clot
Given orally
Provides adequate cover for minor procedures or dental work

The Bleeding History

Personal history
Epistaxis
Bleeding post surgery
Bleeding post dental extraction
Menorrhagia
History of anaemia
Easy bruising
Family history NB


The Bleeding history
Coag. Deficiencies
Prolonged bleeding after trauma and surgery (>24 hrs).
Haemarthroses
Muscle bleeding.

Platelet defects and VWD:

Bruising.
Petechiae or purpura.
Epistaxis.
Menorrhagia
Prolonged post-trauma bleeding

Investigations

TISSUE FACTOR
+TF
VII

TISSUE FACTOR

COMPLEX
XI

IX
X

VIII

V

PROTHROMBIN

THROMBIN

VII
VIIa


FIBRINOGEN

Va
VIIIa
XIa
IXa
Xa
TRIGGER

FIBRIN

Investigation of bleeding disorders
FBC - platelet count
Prothrombin time (PT) - factors V, VII, X
Activated partial thromboplastin time (APTT)- factors VIII, IX, XI, XII
Fibrinogen

Tissue Damage

Tissue Factor Exposure / Thromboplastin
FVII
FVIIa
FX
FXa
II
IIa
Fibrinogen
Fibrin
Fibrin Polymer
Fibrin Clot


FV
FVa

Tissue factor (Extrinsic) Pathway

IIa

Kallikrein

Prekallikrein
FXII
FXIIa
FXI
FXIa
FIX
FIXa
FX
FXa
II
IIa
Fibrinogen
Fibrin
Fibrin Polymer
Fibrin Clot
FVIII
FVIIIa


FV
FVa

Contact factor (Intrinsic) Pathway

IIa
IIa

VWD diagnosis

Coag screen often normal

VWF - quantiative assays

VWF Ricof - functional assay

VWD - diagnosis

Levels increased by menstrual cycle, OCP, pregnancy, smoking, stress, inflammatory disorders

Repeat sampling recommended

equivocal results
minor abnormalities
strong personal or family history