Coagulation disorders

Hereditary coagulation disorders

• Haemophilia A (factor VIII deficiency)

• Haemophilia B (Christmas disease factor IX

deficiency

• Von Willebrand disease (VWD)

• Others are rare

 Haemophilia A
• Most common of hereditary clotting factor deficiencies

• Prevalence is about 30 – 100 per million population

• Inheritance is sex-linked

• A third of cases have no family history and result from

mutation
 Clinical features
• Infants may develop profuse post-circumcision haemorrhage
or joint & soft tissue bleeds & excessive bruising when they
start to be active
• Recurrent painful haemarthroses & muscle haematomas
dominate the clinical course of severely affected patients
• If inadequately treated, lead to joint deformity & disability
• Prolonged bleeding occurs after dental extractions
• Spontaneous haematuria & GIT haemorrhage can occur
• Operative & post-traumatic haemorrhage are life-threatening
• Spontaneous intracerebral haemorrhage is an important
cause of death
 Laboratory findings
The following tests are abnormal
1. APTT
2. Factor VIII clotting assay
• PFA-100, bleeding time and prothrombin time (PT) are normal
• Carriers are detected with DNA probes
• Chorionic biopsies at 8-10 weeks gestation provide sufficient
foetal DNA for analysis
• Foetal blood obtained from the umbilical vein at 16-20 weeks
can be tested for factor VIII levels
• However, this method is only used if DNA analysis is
unimformative
 Treatment
• Bleeding episodes are treated with factor VIII
replacement
• Spontaneous bleeding is usually controlled if the
patients factor VIII level is raised to 30-50% of normal
• Guidelines exist for the plasma level to be achieved
for different types of haemorrhage.
• For major surgery, serious post – traumatic bleeding
or when haemorrhage is occurring at a dangerous
site, the factor VIII level should be elevated to 100%
and then maintained above 50% when acute
bleeding has stopped, until healing has occurred.
• Recombinant factor VIII & plasma-derived
purified factor VIII preparations are available for
clinical use
• 1-Diamino-8-D-arginine vasopressin (DDAVP;
desmopressin) provides an alternative means of
increasing plasma factor VIII level in milder
haemophiliacs
• DDAVP may be taken subcutaneously or nasally
• Local supportive measures include resting the
affected part, application of ice and prevention of
further trauma
 Prophylactic treatment
• Factor VIII concentrates that may be stored in domestic
refrigerators are available
• This has altered haemophilia treatment as haemophiliacs can
be treated at home
• Occurrence of crippling haemarthroses has dramatically
reduced as well as inpatient care
• Patients are now reaching adult life with little or no arthritis
• Prophylaxis is far superior to on-demand treatment
• Regular conservative dental care is advised
• Extreme contact sports/activities are to be avoided
 Inhibitors
• Serious complication of haemophilia is development of
antibodies (inhibitors) to infused factor VIII
• Renders patient refractory to further replacement therapy
• Recombinant activated factor VII (VIIa) and activated
prothrombin complex concentrates (FEIBA – factor VIII
inhibitor by-passing activity) are useful in treatment
• Factor VIIa has a short half-life and frequent doses may be
needed
• In the longer term, immunosuppression with
cyclophosphamide, rituximab, intravenous immunoglobulin &
high-dose factor VIII has also been successful
 Factor IX deficiency (Haemophilia B,
Christmas disease)
• Inheritance & clinical features identical to Haemophilia A
• Distinguished by specific factor assays
• Lower incidence
• Synthesis is vitamin K dependent
• Carrier detection and antenatal diagnosis is performed as for
• haemophilia A.
• Principles of replacement therapy are similar to those for
haemophilia A
• Factor IX has a higher biological half-life & is given less
frequently than factor VIII
• APTT & factor IX clotting assays are useful for diagnosis
• Other tests are normal
 Von Willebrand Disease
• Due to reduced level or abnormal function of von Willebrand
factor (VWF)
• VWF is produced in endothelial cells & megakaryocytes
• Has two (2) roles:
i) Promotes platelet adhesion to subendothelium at high shear
rates
ii) Carrier molecule for factor VIII i.e protects it from premature
destruction
• Chronic elevation of VWF is part of the acute phase response
to injury, inflammation, neoplasia or pregnancy.
 Clinical features
• Most common inherited bleeding disorder
• Inheritance is autosomal dominant
• Women are worse affected than men
• Typically mucous membrane bleeding (e.g epistaxes,
menorrhagia), excess bleeding from superficial cuts &
abrasions, and operative & post-traumatic haemorrhage
• Haemarthroses & muscle haematomas are rare, except in
type 3 disease
 Laboratory findings
1. The PFA-100 test is abnormal. This has largely replaced the
bleeding time
2. Factor VIII levels are often low. If low, a factor VIII/VWF
binding assay is performed
3. The APTT may be prolonged
4. VWF levels are usually low
5. There is defective platelet aggregation by patient plasma in
the presence of ristocetin (VWF/Rco). Aggregation to other
agents (ADP, thrombin or adrenalin) is usually normal
6. Collagen-binding function (VWF:CB) is usually reduced
7. Multimer analysis is useful for diagnosing different subtypes
8. The platelet count is normal except for type 2B disease
(where it is low)
 Treatment
Options are as follows:

1. Local measures and antifibrinolytic agent (e.g tranexamic

acid for mild bleeding)

2. DDAVP infusion for those with type 1 VWD (releases VWF

from endothelial cells 30min after an infusion)

3. High-purity VWF concentrates

 Hereditary disorders of other
coagulation factors
• All these disorders (deficiency of fibrinogen, prothrombin,
factors V, VII, combined V & VIII, factors X, XI, XIII) are rare

• In all, the inheritance is autosomal recessive

• Bleeding only occurs after trauma such as surgery

• Treatment is with fibrinolytic inhibitor, factor concentrate or

fresh frozen plasma
Acquired coagulation disorders
 Acquired coagulation disorders
• The acquired coagulation disorders are more
common than the inherited disorders.
• Unlike the inherited disorders, multiple
clotting factor deficiencies are usual.
 Vitamin K Deficiency
• Fat soluble vitamin K obtained from green vegetables &
bacterial synthesis in the gut
• Deficiency may present in newborns (haemorrhagic disease of
the newborn) or later in life
• Causes of deficiency include inadequate diet, malabsorption
or inhibition of vitamin K by drugs i.e warfarin, which act as
vitamin K antagonists
• Warfarin is associated with a decrease in functional activity of
factors II, VII, IX, X, protein C & S
• Plasma levels remain normal
• Warfarin interferes with the action of vitamin K epoxide
reductase leading to a functional vitamin K deficiency
Haemorrhagic disease of the newborn
• Vitamin K-dependent factors are low at birth

• Fall further in breast-fed infants in first few days of life

• Liver cell immaturity, lack of gut bacterial synthesis & low

quantities in breast milk may all contribute to a deficiency

• Causes haemorrhage usually on second to fourth day of life,

and occasionally during first 2 months
 Diagnosis & Treatment
• PT & APTT both abnormal
• Platelet count & fibrinogen normal with absent fibrin
degradation products
• Prophylaxis – vitamin K given to newborn babies as a single
intramuscular injection of 1mg. It remains the most
appropriate & safest treatment
• In bleeding infants – vitamin K, 1mg intramuscular every 6
hours with prothrombin complex concentrate if haemorrhage
is severe
 Vitamin K deficiency in children or
adults
• Deficiency due to obstructive jaundice, pancreatic or small
bowel disease occasionally causes a bleeding diathesis in
children or adults
• Both PT & APTT are prolonged
• There are low plasma levels of factors II, VII, IX & X
• Prophylaxis: vitamin K 5mg/day orally
• Active bleeding or prior to liver biopsy: vitamin K 10mg slowly
intravenously
• Rapid correction may be achieved by infusion of prothrombin
complex concentrate
 Liver disease
• Multiple haemostatic abnormalities contribute to
a bleeding tendency and may exacerbate
haemorrhage from oesophageal varices
1. Biliary obstruction results in impaired absorption
of vitamin K & therefore decreased synthesis of
vitamin K-dependent factors
2. With severe hepatocellular disease, there are
reduced levels of factor V & fibrinogen &
increased plasminogen activator
3. Functional abnormality of fibrinogen
(dysfibrinogenaemia) is found in many patients
 Liver disease
4. Decreased thrombopoietin production from the
liver contributes to thrombocytopenia
5. Hypersplenism associated with portal hypertension
frequently results in thrombocytopenia
6. Disseminated intravascular coagulation (DIC) may
be related to release of thromboplastins from
damaged liver cells & reduced concentration of
antithrombin, protein C & α₂-antiplasmin
7. The net haemostatic imbalance in liver disease may
be prothrombotic rather than haemorrhagic
 Disseminated intravascular
coagulation (DIC)
• Widespread inappropriate intravascular deposition of fibrin
• Leads to consumption of coagulation factors & platelets
• Consequence of disorders that release pro-coagulant material
into the circulation or cause endothelial damage or platelet
aggregation
• Associated with fulminant haemorrhagic or thrombotic
syndrome with organ dysfunction
• Main clinical presentation is with bleeding, but 5-10% of
patients manifest thrombotic lesions e.g gangrene of limbs
 Pathogenesis of DIC
• Key event is increased activity of thrombin in
the circulation
• May come from tissue factor (TF) release from
damaged tissues on tumour cells or from up-
regulation of TF on circulating monocytes or
endothelial cells in response to pro-
inflammatory cytokines (e.g IL1, TNF,
endotoxin)
 Pathogenesis of DIC
• DIC may be triggered by entry of pro-coagulant
material into the circulation in the following situations:
 severe trauma,
 amniotic fluid embolism,
 premature separation of the placenta
 widespread mucin-secreting adenocarcinomas,
 acute promyelocytic leukaemia (t(15;17)),
 liver disease, severe falciparum malaria,
 haemolytic transfusion reaction & some snake bites
 Pathogenesis of DIC cont….
• DIC may also be initiated by widespread
endothelial damage & collagen exposure (e.g
endotoxaemia, gram negative &
meningococcal sepsis, septic abortion), certain
virus infections & severe burns or
hypothermia
• Thrombin produces large amounts of
circulating fibrin monomers which form
complexes with fibrinogen & interfere with
fibrin polymerization
• The combined action of thrombin & plasmin
causes depletion of fibrinogen & all
coagulation factors
• Intramuscular thrombin also causes
widespread platelet aggregation in the vessels
• The bleeding problems in DIC are
compounded by thrombocytopenia caused by
consumption of platelets
 Clinical features
• Dominated by bleeding, particularly from venepuncture sites
or wounds
• There may be generalised bleeding in the GIT, oropharynx,
into the lungs, urogenital tract & in obstetric cases, vaginal
bleeding may be severe
• Microthrombi may cause skin lesions, renal failure, gangrene
of the fingers or toes or cerebral ischaemia
• Some patients may develop sub-acute or chronic DIC,
especially with mucin-secreting adenocarcinoma
• Compensation by the liver may render some of the
coagulation tests normal
 Laboratory findings
Tests of haemostasis
1. Platelet count is low
2. Fibrinogen concentration low
3. Thrombin time is prolonged
4. High levels of fibrin degradation products such as D-dimers
are found in serum & urine
5. The PT & APTT are prolonged in the acute syndrome
Blood film examination
• Haemolytic anaemia (microangiopathic)
• RBCs show prominent fragmentation because of damage
caused when passing through fibrin strands in small vessels
 Treatment
1. Bleeding
• Supportive therapy with FFP & platelet concentrates is
indicated
• Cryoprecipitate provides a more concentrated source of
fibrinogen
• Red cell transfusions may be required
2. Thrombosis
• Heparin & antiplatelet drugs are considered
• Antithrombin concentrates or protein C may be used to inhibit
DIC in severe cases with sepsis. Activated protein C is reduced
in severe sepsis
• Fibrinolytic inhibitors are contraindicated