Chapter 26 Hereditary Coagulation Disorders

Most common hereditary coagulation disorders:

Haemophilia A (factor 8 deficiency), Haemophilia B/ Christmas Disease (factor 9 deficiency),

VWD

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Haemophilia A (factor 8 deficiency)

This is the most common, has a prevalence of 35-100 per million and sex-linked.

of the patients have no family history and result from mutation

Genetics:

Factor 8 gene is situated near the

tip of the long arm of the X

chromosome

The protein includes a triplicated

region A 1-3, with 30%

homology

Defect is as a result of absence

or low levels of factor 8 in

plasma

Most severe forms of Hemo.A is

caused by missense, frameshift

mutations, deletions or flip-tip

inversions which breaks the end of the X chromosome taking the factor 8 gene with it.

Clinical Features:

Bleeding with mild injury and prolonged bleeding (after dental extraction) i.e increased

PTT

Hemarthroses of the joints or muscles (severs Hemo.A); joint and muscle pain result

reducing mobility

Inadequate treatment leas to joint deformity and disability (clawed toe and deformity of

talipes equinus)

Bleeding in the brain (intracerebral haemorrhage; local pressure causes neuropathy from

entrapment or ischemia necrosis) or GI tract (associated with obstruction as a result of

intramucosal bleeding)

Presence of hemophilic pseudotumors (large encappsulated hematomas (swelling or

clotted blood within tissues) with progressive cystic swelling from repeated

haemorrhage); visualized via MRI

Case file massive haemorrhage in buttock and spontaneous hematoma in buttock

H. Pseudotumors occur in fascial and muscle planes, large muscle groups and long bones

(pelvis or cranium).

In long bones the hematoma is caused by subperiosteal haemorrhage with bone

destruction of bone growth.

Lab findings: abnormal APTT, PFA-100 test and factor 8 clotting assay; BT, PT are normal

Carrier Detection

Disease is detected and mutations identified through use of DNA probes. Chronic biopsies

(removal of blood from fetus for sufficient DNA) taken 8-10 weeks gestation supply viable fetal

DNA or amniocentesis (to collect fetal cells from amniotic fluid)

Treatment:

Replacement of factor 8 and desmopressin (DDAVP) which helps with stimulation and

release of factor 8 from cells.

2-4 fold rise max. at 30-60 mins. The rise in factor 8 is proportional to the resting level.

DDAVP has side effects (Antidiuretic!)

Supportive treatment for hemarthroses and hematomas including rest, ice and prevention

of further trauma

Prophylaxis with factor 8

Gene therapy

Factor levels need to be maintained > 1%

Viral vectors (retroviral and adeno-associated) and non-viral are being used to maintain

these levels

Inhibitors (Antibodies!)

Antibodies develop against factor 8 in 30-40% of cases within the first 50 days of exposure.

Treatment:

with recombinant activated factor 7 and FEIBA for bleeding episodes

Factor 7 along with TF initiate haemostasis in a mechanism that is independent of facto 8

and 9 and thus not affected by their inhibitors

Factor 7 also has a short half-life and so frequent doses are necessary

For long term, immunosuppressive drugs are used (Rituximab, cyclosporine and high

doses of F8)

Factor IX deficiency (haemophilia B, Christmas disease)

Inheritance and clinical features are identical to Hemo. A. The two disorders can only be

distinguished by coagulation factor assays. Also sex-linked, it is four times less common

(1/5) (the gene is four times smaller) and usually milder than haemophilia A.

Synthesis of factor 9 is Vit. K dependent (like that of prothrombin, factor 7,10 and

protein C)

Diagnosis and treatment are similar to haemophilia A, except that factor 9 concentrate is

used for treatment. Advantages? Factor 9 has a longer half-life, less frequent infusions

needed than in Hemo.A.

Lab Findings:

Abnormal APTT and factor 9 clotting assay

PFA-100, BT and PT tests are normal

Von Willebrand Disease

Most common bleeding disorder!

Autosomal dominant and results from missense or null mutations in the VWF gene.

VWD is characterized by a reduced level of VWF or of its abnormal function.

VWF is a large multimeric protein produced by endothelial cells and megakaryocytes.

VWF has two roles: 1. carries factor VIII in plasma preventing premature destruction

2. Mediates platelet adhesion to subendothelium.

Women worse affected than men.

Type 1 accounts for 75% of cases. This is a quantitative partial deficiency, Type 2 is

functional abnormality and Type 3 is a complete deficiency (hemarthroses and muscle

hematomas present). Type 2 is subdivided into 4 types dealing with platelet assoc.

function, factor 8 binding capacity and the presence of high MW VWF multimers.

Clinical Features: bleeding of the mucous membranes, excessive blood loss from cuts and

abrasions and operative and post traumatic bleeding.

Lab Findings: abnormal PFA-100 test, low factor 8, prolonged APTT, low VWF, defective plt

aggregation in the presence of ristocetin

Treatment: VWF concentrates DDAVP infusions and antifibrinolytic agents

.

Acquired disorders

Vitamin K deficiency

Vitamin K is required to activate factors II, VII, IX and X and protein C and S by -

carboxylation.

It is fat-soluble and derived from vegetables in food and bacterial synthesis (stomach).

Deficiency occurs in patients on poor diets, in biliary tract disease and with intestinal

malabsorption, those taking inhibitory drugs like Warfarin (Vit K antagonist). Warfarin

interferes with the action of Vit K epoxide reductase leading to a functional in Vit K

deficiency.

Haemorrhagic Disease of the Newborn

Newborn infants are at an increased risk of bleeding because of liver cell immaturity, lack of gut

bacterial synthesis of Vit K and low levels of vitamin K.

Diagnosis: abnormal Pt and APTT, plt count and fibrinogen are normal with absent fibrin

degrading products

Treatment: prophylaxis,1mg Vit K IM

Vit. K deficiency in children and adults

Deficiency results from pancreatic or small bowel disease or from obstructive jaundice.

Clinical features: bleeding diathesis

Diagnosis:

PT and APTT are prolonged

Low plasma levels of factor 2,7,9 and 10

Treatment: prophylactic (5mg/day Vit K; oral) or 10 mg IV before liver biopsy or for active

bleeding; infusion of prothrombin complex concentrate

Liver Disease

Liver disease leads to defects of coagulation, platelets and fibrinolysis.

1. Impaired Vit K absorption leading to decreased factors ^ synthesis (biliary obstruction)

2. Reduced levels of factor 5 and fibrinogen and ^ plasminogen activator (hepatocellular

disease)

3. Decreased thrombopoietin production contributes to thrombocytopenia

4. Thrombocytopenia (hypersplenism)

5. DIC (thromboplastin release, reduced antithrombin, protein C and alpha antiplastin)

DIC

Widespread fibrin deposit in the circulation with the consumption of coagulation factors and

platelets

Clinical features: bleeding in GI, oropharynx, lungs etc; thrombotic lesions (5-10%), gangrene

of fingers or toes, cerebral ischemia

Pathogenesis: increased activity of thrombin, more than that removed by natural anticoagulants.

DIC triggered by entry of procoagulatnt material into the circulation from trauma, embolism or

liver disease.

DIC may be initiated by widespread endothelial damage and collagen exposure

Intravascular thrombin: deposits fibrin in microcirculation, produce large amounts of

circulating fibrin monomers which form complexes with fibrinogen and interfere with fibrin

polymerization; causes widespread plt aggregation in the vessels

Lab findings:

Blood fails to clot in acute syndrome (fibrinogen deficiency)

Plt count low, fibrinogen conc. Low, TT, PT and APTT prolonged, D-dimers high (fibrin

degradation products)

Blood film shows HA and RBC fragmentation

Treatment: cryoprecipitate or fresh frozen plasma and plt concentrate (bleeding); heparin or

anti-plt drugs to inhibit coagulation (thrombosis); antithrombin concentrate or recombinant

activates Protein C to inhibit DIC (severe cases)

Coagulation deficiency caused by antibodies

Alloantibodies to factor 8 occur in 5-10% of haemophiliacs

Autoantibodies to factor 8 (IgG) result in bleeding syndrome and occur rarely postpartum

in immunological disorders (rheumatoid arthritis), cancer or old age.

Treatment: immunosuppression, factor replacement, recombinant factor 7 or FEIBA (activated

prothrombin complex concentrate)

Lupus anticoagulant (inhibitor) interferes with lipoprotein dependent stages of

coagulation

In 10% of systemic lupus patients and patients who have antibodies to lipid-containing

antigens (cardiolipin)

Massive transfusion syndrome

Blood loss results from reduced plt levels, coagulation factors and inhibitors.

Management/treatment: plt concentrates (maintains plt count >50 or 80 x1069/L);

recombinant activated factor 7 (RCT); cryoprecipitate