Bleeding Disorders: Vitamin-K Deficiency, Disseminated Intravascular Coagulation (DIC), and Excess Fibrinolysis

Acquired Coagulation Disorders

  • Bleeding disorders that occur secondary to other conditions.
  • More common than inherited disorders.
  • Associated with multiple clotting factors deficiency.
  • Caused by:
    • Vitamin K deficiency
    • Disseminated intravascular coagulation (DIC)
    • Excess fibrinolysis
    • Liver diseases

Vitamin K

  • A group of structurally similar, fat-soluble vitamins.
  • Sources:
    • Many vegetables & some meat, particularly liver.
    • Intestinal synthesis by bacteria in the large intestine.
  • Absorption:
    • Dietary vitamin K is absorbed in the duodenum and jejunum and requires bile salts for its absorption.

Vitamin K Function

  • Vitamin K is required for the synthesis of factors II, VII, IX and X, and proteins S and C.
  • Vitamin K is required to complete the molecules of these factors so that they can bind calcium and combine with phospholipid.
  • The synthesis of these factors occurs in the liver.

Disorders of Vitamin K Dependent Factors

  • Occurrence: Vitamin K dependent factors deficiency is the most common coagulation factor deficiency.

Causes of Vitamin K Deficiency

  • Deficiency can occur due to:
    • Dietary deficiency
    • Poor absorption of dietary vitamin K from the intestine
    • Poor clotting factor production due to liver disease
    • Interference with vitamin K metabolism by chemicals or drugs “Warfarin” → (functional Vit K) deficiency

Signs & Symptoms of Vitamin K Deficiency

  • Easy bruising
  • Epistaxis
  • Excessive bleeding from wounds, injection, or surgical sites
  • Heavy menstrual periods
  • Presence of blood in the urine and stool

Laboratory Testing for Vitamin K Deficiency

  • Platelet count: normal
  • Bleeding time: normal
  • PT & APTT are prolonged
  • Corrected by aged plasma
  • Not corrected by absorbed plasma
  • TT normal
  • FDP: normal
  • D-dimer: normal

Differential Diagnosis of Vitamin K Deficiency

  • Dietary Deficiency
    • Poor diet and no evidence of other causes
    • TT (Fibrinogen) normal, platelets normal
    • Responds to injections of Vitamin K
  • Malabsorption
    • Evidence of poor intestinal function
    • TT (Fibrinogen) normal, platelets normal
    • Responds to vitamin K injections
  • Liver Disease
    • Clinical and laboratory evidence of liver disease.
    • Fibrinogen low, platelets low-normal.
    • Does NOT respond to vitamin K injections
    • May require transfusion of clotting factors such as fresh frozen plasma, Vitamin K dependent factor concentrates.
  • Coumarin Drug Overdose
    • History of drug administration
    • Fibrinogen and platelets normal
    • Responds to drug withdrawal and vitamin K injections.
  • Haemorrhagic Disease of the New-born
    • Some infants have poor liver function (immature)
    • Breast milk has low vitamin K
    • Respond to vitamin K injections - given to all babies at birth

Management and Treatment of Vitamin K Deficiency

  • The treatment depends on the cause of the deficiency.
  • Having a good diet and enough food rich with vitamin K helps manage the disorder.
  • Also, treating the cause of malabsorption helps treat the disorder.

Disseminated Intravascular Coagulation (DIC)

  • Disseminated → All, systemic, generalized
  • Intravascular → within blood vessels
  • Coagulation → fibrin formation, clot formation
  • So, DIC is “Fibrin formation within all blood vessels” Resulted from excessive activation of coagulation (uncontrolled & not localized)

Definition of DIC

  • A condition where the normal inhibition of coagulation fails.
  • Small clots form in all blood vessels.
  • It is a symptom, not a disease.
  • Life-threatening condition.

Results of DIC

  • Consumption of coagulation factors & platelets which →leads to bleeding
  • Destruction of red cells in the small blood vessels→ microangiopathic haemolysis “MAHA”
  • Production of fibrin degradation products (FDPs)
  • So, coagulation & fibrinolysis occur simultaneously, & either one may predominate at any given time.

Causes of DIC

  • There are many causes, including:
    • Obstetric emergencies
    • Intravascular haemolysis
    • Cancer
    • Septicaemia
    • Viral infections
    • Acute liver disease
    • Burns
    • Snake bite
  • The key triggering event→
    • An increase in tissue factor (TF) expression, which occurs on monocytes & endothelial cells.
    • In response to cytokines, endotoxins, IL 1, TNFα

Pathophysiology of DIC

  • Over activation of the coagulation mechanism leads to excessive thrombin generation Fibrin clots in small blood vessels→ thrombosis Consumption of FVIII, FV Fibrinogen & Platelets Activation of Plasmin- Excess fibrinolysis
  • Hemolysis of RBCs
  • Anemia with fragmented cells
  • Renal failure
    • Bleeding
    • Thrombocytopenia
    • Prolonged PT, APTT, TT.
    • Low fibrinogen
    • Increased FDP
    • Increased D dimer
      • CAUSE e.g. septicaemia Excess thrombin formation and coagulation

Clinical Features of DIC

  • There are 3 clinical states of DIC:
    • Acute DIC (uncompensated)
      • Rate of consumption > rate of synthesis
      • Bleeding tendency
    • Chronic DIC (compensated)
      • Rate of consumption = rate of synthesis
      • Intermediate between bleeding & thrombosis
    • Thrombotic state
      • Rate of coagulation > rate of fibrinolysis
      • Thrombotic complications dominate

Acute DIC

  • Develops rapidly over hours to a few days
  • Causes: snake venom, tissue injury, obstetric complications, liver disease, infections
    • “Many bleeding sites” is the major feature present in the acute form of DIC
    • Skin manifestations are common
    • Thrombotic complications are unusual (<10%)
    • Mortality rate high (50 - 70)%

Chronic DIC

  • A form that is resulted from a weak or intermittent activating cause
  • Causes: malignancy, liver diseases, intrauterine fetal death..
  • The consumption & production of coagulation factors are nearly balanced
    • So, minimal manifestations will develop
    • Clinical features: are in intermediate between acute & thrombotic state
    • Lower mortality rate

Laboratory Diagnosis of DIC

  • CBC
    • Low platelet count
    • Hb low: Hemolytic anemia
  • Blood Film
    • Fragmented cells
    • High reticulocyte count
  • Coagulation Screen
    • PT, APTT, and TT prolonged
    • Fibrinogen - low
    • Correction experiments - variable results
  • Fibrinolysis screen:
    • FDPs/ D-dimer increased

Treatment of DIC

  • Depends upon severity, but has four phases:
    • Treat primary cause
    • Prevent further coagulation
      • Heparin low doses→ can lead to more bleeding
    • Replace factors consumed
      • Fresh-frozen plasma, platelets, red cells → can lead to more thrombosis
    • Inhibit fibrinolysis
      • Anti-fibrinolytic drugs → epsilon-amino-caproic acid, tranexamic acid

Acquired Coagulation Disorders & Excess Fibrinolysis

  • Acquired coagulation disorders:
    • Bleeding disorders occur secondary to other disorders
  • Are caused by:
    • Disorders of the vitamin k dependent factors (FII, FVII, FIX and FX and PS & PC)
    • Disseminated intravascular coagulation (DIC)
    • Excess fibrinolysis
    • Liver disease

Recap: Normal Fibrinolysis

  • Fibrinolysis as one and last component of haemostasis.
  • Part of the normal regulatory mechanism to dissolve clots “fibrin”.
  • Plasmin→ the enzyme that breaks down fibrin.
  • Plasminogen→ the inactive form of plasmin

Normal Fibrinolysis

  • Plasminogen is activated by a substance released from health endothelial cells → tPA.
  • The enzyme plasmin cuts:
    • Fibrin→ at various places
    • FV, FVIII & fibrinogen → when present in excess amount
  • The products of fibrin & fibrinogen breakdown → fibrin/fibrinogen degradation products (FDPs).

Excess Fibrinolysis

  • Excess fibrinolysis “hyper fibrinolysis” → increase activity of fibrinolysis
  • May be: Primary or Secondary
    • Primary may be: hereditary or acquired

Secondary Fibrinolysis

  • Excess fibrinolysis resulted from excess activation of coagulation (DIC)→
    • Because it follows excess clotting (haemostatic fibrinolysis)
  • Primary fibrinolysis: excess fibrinolysis NOT caused by excess clotting
    • Pathologic condition occurs with the presence of:
      • Excess activators &/or
      • Decreased inhibitors that causes → hyperplasminemia “high plasmin in blood” à excess fibrinolysis

Causes of Primary Fibrinolysis

  • Primary fibrinolysis can be caused by many systemic conditions such as:
    • Heat stroke
    • Hypoxia
    • Major surgery
    • Barbiturate overdose
    • Severe liver disease

Pathophysiology of Primary Fibrinolysis

  • The results of excess fibrinolysis:
    • Dissolved clots
    • Low fibrinogen
    • Low FV & FVIII
    • Resulted in bleeding tendency

Laboratory Investigation of primary vs DIC

  • It is important to distinguish between DIC & primary fibrinolysis.
  • Screening tests:
    • CBC: Platelets: normal → in DIC: low
    • Blood film: no hemolysis or fragmentation as seen in DIC
    • PT, APTT & TT: prolonged → but not as bad as DIC..
    • Fibrinogen assay: low
    • FDPs: high → DIC same
    • D-dimer: negative → DIC positive

Tests of Fibrinolysis

  • FDP detection
  • D-dimer assay → Latex agglutination immunoassay à see Practical handout 7
  • Special Tests; Euglobulin Clot Lysis Time

D-Dimer Assay

  • D-dimer: is the breakdown of the stable insoluble fibrin clot à fibrin degradation product; So:
    • Normal in fibrinogen break downà primary fibrinolysis
    • Specific for fibrin break downà secondary fibrinolysis
  • So, it's only increased after excessive activation of coagulation & fibrin formation
  • Aim→ help to diagnose thrombosis
  • Principle: →Latex agglutination immunoassay. →Slides coated with monoclonal abs for soluble D-dimer molecules.
  • Results: →Normal range: < 500 ng/ml. → Positive in DIC & deep vein thrombosis (DVT) & pulmonary embolism (PE) “thrombosis”

Special Tests; Euglobulin Clot Lysis Time

  • This test is used to detect the activity of fibrinolysis
  • Principle
    • When plasma is diluted in cold acetic acid (pH 5.4)→ a precipitate forms.
    • Precipitate is “euglobulin” → contains important fibrinolytic factors plasminogen, plasminogen activator (tPA) & fibrinogen.
    • Precipitate is dissolved in buffer (pH 7.4)
    • Thrombin is then added → a clot forms
    • The time taken for the clot to dissolve at 37°C→ is a measure of the fibrinolytic activity of the plasma.

Summary; Euglobulin Clot Lysis Time

  • Precipitate with acetic acid
  • Centrifuge to get precipitate
  • Dissolve precipitate in buffer
  • Clot with thrombin
  • See how long the clot takes to dissolve
  • Controls
    • Run normal controls

Euglobulin Clot Lysis Time

  • Reference range:
    • 90 - 240 minutes→ Normal
    • < 90 minà excess fibrinolysis “either primary or secondary”à bleeding risk
  • Interpretation
    • Fibrinogen levels must be adequate, or clot does not form properly & then dissolves quickly.
    • This occurs in DIC → short times < 90 min → indicates excess fibrinolysis.

Important Note on Fibrinolytic Drugs

  • Fibrinolytic drugs are used to enhance temporally fibrinolysis
  • Fibrinolytic substances → tPA, streptokinase
  • They are given in the following:
    • Heart attack → to dissolve the thrombus blocking the coronary artery
    • After a stroke→ to allow blood flow back to the affected part of the brain
    • In a massive pulmonary embolism & others