Introduction:

• All of these disorders present with mild bleeding tendency except for factor X and factor XIII deficiency
• F XIII deficiency alone causes frequent miscarriages
• Rec Factor VIIa can be used in any of them. Dose- 15- 200mcg/ kg every 2-6 hrly, depending on the severity of bleeding.
• All acquired factor deficiencies are discussed under “other acquired coagulation disorders” chapter.

Fibrinogen (Factor 1) Deficiency

Introduction:

• Prevalance-1:1 000 000
• 2 Forms
  • Type I-  2 Subtypes
    • Afibrinogenemia – plasma and platelet levels of fibrinogen are not measurable
    • Hypofibrinogenemia- Fibrinogen levels are decreased to less than 1.5g/L
  • Type II- Dysfibrinogenemia – Low clottable fibrinogen but levels in plasma are normal

Etiology:

• Mutation of any one of 3 genes on Chromosome 4 which code for 3 chains of fibrinogen- 
  • A- alpha -(FGA gene)
  • B- Beta -(FGB gene)
  • G- Gamma- (FGG gene)
• More than 80 mutations have been identified
• Types of defects observed
  • Impaired release of fibrinopeptides
  • Defect in fibrin polymerization
  • Defective factor XIII mediated cross linking
  • Hypo-dysfibrinogenemia

Pathogenesis:

• Bleeding due to
  • Defective platelet aggregation (Fibrinogen binds to GpIIb and IIIa and facilitates platelet aggregation)

• Defect in normal clot formation
• Thrombosis due to 
  • Impaired tissue type plasminogen activator mediated fibrinolysis
  • Defective fibrinogen is resistant to fibrinolysis
  • As fibrin has antithrombin activity, there is higher thrombotic tendency

Clinical features

• Bleeding 
  • Usually have umbilical cord bleeding
  • Also have mucosal bleeding
  • Joint bleeds are infrequent
  • Susceptible for spontaneous rupture of spleen.
  • Hemoperitonium after rupture of corpus leuteum
• Thrombosis
  • Both arterial and venous thrombosis are seen.
  • Thrombosis is common with concurrent thrombophilic risk and after replacement therapy
• Recurrent first trimester abortions (At 5-8 weeks)
• Poor wound healing
• Liver disease- Due to retention of abnormal fibrinogen in hepatocytes

Investigations:

• PT- Prolonged
• APTT- Prolonged
• TT- Prolonged
• S. Fibrinogen levels- Decreased in type 1 disease (Normal 150-400mg/dL)
• ESR- Very low
• Genotype analysis to identify the mutation
• Functional fibrinogen assessment- Decreased levels

Differential diagnosis

• Afibrinogenemia
  • DIC
  • Primary fibrinolysis
  • Liver disease
  • Drugs- Thrombolytic agents, L-Asparginase
  • Artefactual in samples that have clotted
• Dysfibrinogenemia
  • Liver diseases- Cirrhosis, chronic hepatitis etc
  • L-Asparaginase treatment
  • Rarely- Pancreatitis, paraneoplastic syndrome, renal cell carcinoma

Treatment

• Replacement therapy in the event of bleeding episodes
  • Fresh frozen plasma- Has problem of volume overload and TRALI
  • Cryoprecipitate-
    •  Higher chances of thrombosis due to high concentrations of factor VIII and vWF. 
    • Dose- 1-2 bags/10 kg
  • Fibrinogen concentrates
    • Provided after viral inactivation
    • Dose- 50-100mg/kg every 2-4 days- to maintain fibrinogen level >1g/L.
• Antifibrinolytic agents for mucosal bleed
• Local measures such as fibrin glue following dental extraction
• Menorrhagia- Estrogen- progesterone containing preparations
• Oral iron replacement- For iron deficiency anemia
• Routine vaccination against hepatitis.

Primary prophylaxis

• Started in some at early age to prevent bleeding episodes
• Given during pregnancy to prevent miscarriages
• Patients who have experienced CNS bleeds must receive prophylaxis
• Replacement is given once in 7 to 14 days.

Prothrombin(Factor 2) deficiency

Introduction

• Gene on chromosome- 11
• Prevalence: 1:2000000
• 2 forms
  • Hypoprothrombinemia – concomitantly low levels of activity and antigen
  • Dysprothrombinemia – Normal synthesis of a dysfunctional protein

Etiology:

• Defect in 21 kb gene is located on Chromosome 11, which contains 14 exons encoding prothrombin
• About 50 mutations have been identified.

Clinical features

• Hemarthroses
• Muscle hematoma
• Mucocutaneous bleed

Investigations:

• PT- Normal/ prolonged
• APTT- Normal/ prolonged
• Functional levels of prothrombin- Decreased
• Plasma factor II antigen immunoassay- Decreased in type 1

Treatment: Needed only if there is a major bleed

• Replacement- Prothrombin complex concentrates. 
  • Dose- 20-30 factor 9 units/ kg of PCC- Every 2-3 days interval till bleeding stops.
  • May cause thrombosis due to presence of some activated clotting factors. So small, frequent doses are better.
  • If PCC is not available give loading dose FFP- 15-20ml/kg followed by 3-5ml/kg/day
• If surgery is planned, single transfusion is sufficient, as t ½ is 60-70 hours.

Factor V Deficiency (Parahemophilia)

Introduction:

• 2 forms
  • Type I - Deficiency of F V activity and antigen
  • Type II - Normal antigen levels, but dysfunctional protein

Etiology:

• Mutation in F V gene on chromosome 1q23
• More than 100 different mutations have been identified.

Clinical features

• Bleeding tendency- Both mucosal and deep

Investigations

• PT and APTT- Prolonged
• TT- Normal

Treatment

• Mild mucosal bleed- Tranexamic acid and local hemostatic measures
• Severe bleed/ planned surgery- Fresh frozen plasma- Loading dose- 20ml/kg, then 5-10ml/kg every 12hrly for 7 days.
• Add platelet transfusion (which is rich in factor V) if there is persistent bleeding in spite of FFP.

Factor V- Quebec

• Normally platelets take up factor V from plasma and store it in alpha granules
• This is defective in Quebec disorder
• There is low platelet Factor V activity
• Autosomal dominant inheritance
• Mild thrombocytopenia
• Severe bleeding manifestations

Factor VII deficiency

Introduction:

• Gene on chromosome- 13
• Prevalence- 1:500 000
• Most common autosomal recessive coagulation disorder
• 0.05% of normal F VII concentration i.e. 5 m mol/L is sufficient to induce clot formation

Etiology:

• Mutation of F VII gene on chromosome 13q34
• More than 180 mutations have been identified so far
• Sometimes it can be associated with Dubin Johnson syndrome. 

Clinical features:

• Variable and poorly correlates with plasma levels of F VII
• Usually mild bleeding tendency- Generally mucosal bleed and prolonged bleeding following injury.
• Some develop venous/ arterial thrombosis

Investigations- Should be done after supplementation of vitamin K

• PT- Prolonged
• Factor VII activity- Decreased
• Measurement of Factor VII antigen levels by ELISA

Differential diagnosis

• Liver disease
• Vitamin K deficiency
• Oral anticoagulants
• Lupus anticoagulant
• Paraneoplastic syndrome associated with atrialmyxoma and Wilmtumor

Treatment: Needed for severe bleeds and if surgery is planned

• Mild- Tranexamic acid
• Moderate to severe bleed- Replacement therapy
  • Prothrombin complex concentrates: Dose- 8-40 units/ kg- at 4-6 hrly intervals
  • If plasma is used- Loading dose- 15ml/kg- then 4ml/kg every 6 hrly for 7-10 days. Diuresis is needed to decrease volume overload.
  • RecFVIIa
• Local haemostasis
• Secondary prophylaxis is given to patients with CNS bleed
  • RecVIIa- 20-30microgm/kg- given 2-3 times in a week

Combined deficiency of F V and F VIII

Etiology:

• Mutation in LMAN 1 gene  on chromosome 18 (75% cases)
  • LMAN1 acts as chaperone in the intracellular transport of both factors V and VIII
• Mutation in MCFD2 gene on chromosome 2 (15%)
  • MCFD2 forms calcium dependent 1:1 stechiometric complex with LMAN1 and acts as cofactor for LMAN1

Clinical features: 

• Mild bleeding tendency

Treatment:

• Minor bleeds- Tranexamic acid and local measures
• Severe bleed/ surgical procedures
  • FFP as replacement for Factor V
  • Cryoppt as replacement for Factor VIII

Factor X deficiency

Etiology:

• Missense mutation of F X gene on chromosome 13
• Over 95 mutations have been identified

Clinical features – Very severe bleeding tendency (when activity is <1%)

• Hemarthrosis
• Hematoma
• Bleeding from umbilical cord stump
• Mucus membrane bleed

Investigations

• Prolonged PT and APTT
• PT alone is prolonged if mutation causes defect only in the tissue factor pathway
• Only APTT is prolonged if mutation causes defect in the intrinsic activity of factor X
• Specific factor X assay

Differential diagnosis

• Oral anticoagulants
• Vitamin K deficiency
• Liver diseases
• DIC
• Inhibitors
  • Post infections
  • Malignancies
  • Systemic amyloidosis (AL type)

Treatment

• Mild bleeding- Tranexamic acid
• Moderate/ severe bleeding/ planned surgery- Replacement therapy
  • Prothrombin complex concentrates- Dose- 15-20 Factor 9 units/ Kg- OD
  • FFP- Loading dose- 10-20ml/Kg, then, 3-6ml/Kg every 12-24hrs.

Prophylaxis:

• Given if there is personal or family history of severe bleed
• Dose- PCC- 20-30IU/Kg- Twice a week.

Factor XI deficiency (Hemophilia C)

Etiology and epidemiology:

• Gene is located on chromosome-  4
• 3 mutations have been described
• Prevalence- 1:1 000 000
• Seen mostly in Jewish population

Clinical features:

• Mild bleeding tendency, especially injury related
• Association with Goucher disease has been described

Investigations

• PT- Normal
• APTT- Prolonged
• Factor XI level measurement by ELISA- Decreased

Treatment- 

• Minor bleed- Tranexamic acid
• Moderate/ severe bleed
  • FFP- 15-20 ml/kg as loading dose, 5 ml/kg every 15-24 hrly then 10 days
  • High risk of thrombosis with factor XI concentrates, hence they are avoided.

Factor XIII deficiency

Etiology and epidemiology:

• Normally it crosslinks alpha & gamma fibrin chains, resulting in a stronger clot with an increased resistance to fibrinolysis
• Gene is located on chromosome6 (subunit A) and 1 (subunit B)
• Prevalence: 1:2 000 000
• Usually missense mutations are seen

Clinical features: 

• Severe bleeding tendency- Hematoma, hemarthrosis
• Following trauma- Bleeding is usually delayed (12-36 hrs post injury is characteristic)
• Bleeding from umbilical stump
• Recurrent abortions
• Impaired wound healing
• Intra-abdominal bleeding at first ovulation

Investigations

• PT and APTT- Normal
• FDP- Increased
• TT- Minimally prolonged
• Clot solubility test- Early clot dissolution. Done using 5M Urea/ Dilute monochloro acetic acid/ Acetic acid
• Factor XIII activity assay
• Factor XIII- A subunit measurement by ELISA
• Ammonia release assay

Differential diagnosis

• Alpha 2 antiplasmin deficiency
  • Normal PT, APTT with positive clot solubility test
  • Bleeding manifestations are minimal
• Inhibitors to factor XIII
  • Seen in SLE, Lymphoproliferative disorders

Treatment

• FFP- 15ml/kg- every 4-6 weeks
• Cryoppt- 1unit/15kg- every 3-4 weeks
• Factor XIII concentrates- 10-20units/kg every 5-6 weeks
• More frequent replacement is needed during pregnancy to prevent fetal loss

Prophylaxis

• Better to give as risk of IC bleed is high
• 20-40IU/kg every 28 days

Deficiency of all vitamin K dependent factors

• Type I- Mutation of gene encoding carboxylase, that is involved in gamma carboxylation of glutamic acid residues.
• Type II- Mutation in vitamin K- 2-3 epoxidereductase gene
• Deficiency of Factors- II, VII, IX, X, Protein C, Protein S, Protein Z and osteocalcin
• Severity of bleeding varies considerably
• PT and APTT- Prolonged
• Treatment
  • Large doses of Vitamin K- 20mg- IV every week or PO- 20mg-Daily
  • For acute episodes of bleeding
    • FFP
    • PCC
    • Tranexamic acid

Deficiency of contact factors (Factor 12, prekallikrein, HMWK)

• They are required for the normal activation of factor XI in the “contact phase”, that initiates coagulation in APTT assay
• In these deficiencies, although APTT is prolonged, there is not abnormal hemostasis, even with major surgery/ injury
• Hypothesis
  • These proteins do not participate in haemostasis
  • Redundant mechanisms compensate for their absence
• No treatment is required, to prepare patients for invasive procedures
• If they need anticoagulation NOACs may be used