Bleeding Disorders

(CBD)
R.N- 284, 287
Coagulation Cascade and Fibrinolytic Pathway
Three mechanisms of bleeding disorders
I. Vascular disorders
II. Platelet disorders
III. Coagulation Factor disorders
I. Vascular Disorders
1. Congenital vascular disorders
(1) Hereditary haemorrhagic telangiectasia
- Autosomal dominant
- Mutation in 1 of 3 genes: ENG, ALK1 or SMADH (Involved in blood vessel
development)
- Present either with recurrent bleeding or with Iron deficiency due to GI
bleeding.
(2) Ehler Danlos disease
- Autosomal dominant (Rare, 1:100,000)
- Defect in type 3 collagen  fragile blood vessels and organ membranes 
bleeding and organ rupture
- Typical skin changes and facial appearances
- Should be considered if there is History of bleeding with normal laboratory
tests.
2. Accquired vascular disorders
(1) Purpura d/t infections
- Damage to vascular endothelium,
- Meningococcal septicemia is particularly characteristic
(2) Henoch-Schőnlein purpura
- Occurs mainly in children,
- Type 3 hypersensitivity,
- Often preceded by a/c URTI (Purpura on legs and buttocks)
- Abdominal pain, arthritis, haematuria and glomerulonephritis also occur,
- Recovery is usually spontaneous but some patients develop Renal failure.
(3) Senile purpura and Purpura d/t steroids
- Mainly d/t atrophy of vascular supportive tissue
(4) Scurvy
- Vitamin C deficiency  affect collagen synthesis
II. Platelet disorders
A. Qualitative disorders
(i) Congenital: Disorders of membrane glycoprotein
(ii) Accquired: Drugs (NSAIDs)
B. Quantitative disorders
(i) Decreased production
• BM aplasia: aplastic anemia
• BM infiltration: leukemia
(ii) Increased destruction
• Immune mediated: ITP
• Increased consumption: DIC
• Thrombotic microangiopathies: HUS, TTP
(iii) Abnormal Platelet distribution
• Hypersplenism
II. Platelet disorders
• Bleeding can be due to
1. Thrombocytopenia, &
2. Abnormal platelet function.
1. Thrombocytopenia
• caused by reduced platelet production
in the bone marrow, excessive
peripheral destruction of platelets or
sequestration in an enlarged spleen.
Immune Thrombocytopenic Purpura (ITP)
• Acquired quantitative platelet defect d/t autoimmune destruction of
mature platelets in the peripheral blood.
• Age: Acute ITP  in children 2-6 yrs, Chronic ITP  Usually in adults
• Sex: Female > Male
• Onset: sudden or insidious
• Risk factors:
- Acute ITP: History of recent viral infection
- Chronic ITP: autoimmune disorders such as SLE, thyroid disease and
autoimmune haemolytic anemia (Evans syndrome), chronic
lymphocytic leukaemia and solid tumours, infections such as HIV.
• Clinical features
- Bleeding  spontaneous or minor trauma
Skin: petechiae, purpura, ecchymosis
Mucosa: epistaxis, gum bleeding, H&M
Organ: ICH if severe
- Anemia is proportionate to the degree of bleeding.
- Spleen is palpable only in 10% of patients.
• Investigations
1. Bleeding time: prolong
2. Clotting time: normal
3. Blood for CP: isolated thrombocytopenia
4. BM biopsy: normal or increased no. of Megakaryocytes (Not usually
done)
5. Platelet antibodies: 70-90%
• Management
A. Children (acute ITP)
- Children do no usually require treatment. (Should be reserved for severe
bleeding or urgent surgery.
- Moderate to severe cases (plt < 25×109): Prednisolone 1mg/kg daily
- IV immunoglobulin, anti D in Rh (+) patients
B. Adults (chronic ITP)
First line therapy
- Prednisolone 1mg/kg daily
- IV immunoglobulin IgG 1g/kg
Second line therapy
- Splenectomy
- Rituximab
- Thrombopoietin r/c agonist
- Platelet transfusion
2. Platelet function disorders
• usually associated with excessive
bruising and bleeding and with
thrombosis in some cases.
• The platelet count is often
normal and the bleeding time is
prolonged.
• If there is serious bleeding or if
the patient is about to undergo
surgery, drugs with antiplatelet
activity should be withdrawn and
any underlying condition should
be corrected if possible.
Aplastic anemia
• Risk factors: drugs, chemical exposure, radiation, infection
• Clinical features
- Bleeding: skin, mucosa and organ bleeding
- Anemia: Pallor is out of proportionate to the amount of bleeding, progressive
anemia and anemic HF
- Infection: prolonged or recurrent fever, Recurrent infection
- No organomegaly, Lymphadenopathy and Bone pain
• Investigations
- Blood for CP: Pancytopenia
- BM: dry tap, replaced by fat
• Management
(i) Immunosupressants: cyclosporine, ALG
(ii) Bone marrow Stimulants: Danazol, Androgens
(iii) Allogenic BM transplant
Acute Leukemia
• Risk factors: radiation, cytotoxic drugs
• Clinical features
- Anemia, infection, bleeding
- Hepatomegaly, Lymphadenopathy
- Bone and joint swellig and tenderness, sternal tenderness
- Loss of wt., Loss of appetite
- Others: CNS, Testes, Eye, DIC, Gum hypertrophy
• Investigations
- Blood for CP: Hb% reduced, Platelet reduced, high WBC count (majority Blast
cells)
- BM: hypercellular, leukemic blast cells > 20%
• Management
(i) Chemotherapy
(ii) Radiotherapy, Immunotherapy, BM transplant
Disseminated intravascular coagulation (DIC)
• Risk factors: septicemia
• Clinical features: Bleeding at skin, mucosa, internal organs and
venepuncture sites.
• Investigations
- Blood for CP: anemia, thrombocytopenia, WBC count: variable
- BT and CT: Prolong, Fibrinogen: decreased, Fibrin degradation products:
increased.
• Treatment: Fresh blood, FFP
III. Coagulation factor disorders
1. Congenital  Hemophilia A, B
2. Accquired  DIC, Liver d/s, Anticoagulant overdose
1. Hemophilia
• A group of congenital coagulation disorders leading to an abnormal
bleeding tendency d/t genetically determined sex linked recessive
defect.
• Hemophilia A: Factor VIII deficiency (True hemophilia)
• Hemophilia B: Factor IX deficiency ( X’mas d/s)
• Incidence:
• Hemophilia A: 1 in 5,000 male
• Hemophilia B: 1 in 300,000 male
• X lined Recessive: If a female carrier has a son, he has a 50% chance of
having hemophilia; a daughter has a 50% chance of being a carrier. All
daughters of men with hemophilia are carriers and the sons are normal.
Hemophilia A
• Clinical Features
- The clinical features depend on the
level of factor VIII. The normal level of
factor VIII is 50–150 IU/dL.
 Levels of <1 IU/dL (severe hemophilia):
frequent spontaneous bleeding from
early life, typically into joints and muscles
 crippling joint deformity.
 Levels of 1–5 IU/dL (moderate
hemophilia): severe bleeding following
injury and occasional spontaneous
bleeds.
 Levels of >5 IU/dL(mild hemophilia):
bleeding only after injury or surgery.
Diagnosis in this group can often be
delayed until quite late in life.
• Investigations
- Bleeding Time: Normal, Clotting Time: Prolong
- APTT: Prolong
- Factor VIII, IX assay
- Blood for CP: Platelet count Normal or increase
• Management
- In high income countries,
 Prophylaxis using coagulation factor concentrates or, in haemophilia A,
by a bispecifc monoclonal antibody called emicizumab that mimics factor
VIII activity.
 There are new products produced by Fc fusion and
pegylation/glycopegylation that extend the half-life of the coagulation
factor to the degree.
- In low and middle income countries,
 Factor VIII concentrate IV infusion
 Resting of the bleeding site with either bed rest or a splint reduces
continuing haemorrhage
 Physiotherapy after bleeding is settled
 Hepatitis A and B immunization (For all non-immune potential recipients
of pooled blood products)
- For surgery, levels should be kept to normal until healing has
occurred.
- In patients with a baseline level of factor VIII of over 10 IU/dL,
synthetic vasopressin (Desmopressin) IV, SC or IN can be used.
 3–5-fold rise in factor VIII and VWF levels.
 Avoids the complications.
 Dose: 0.3µg/kg IV or SC, 300 µg.
 On repeated administration, patients need to be monitored for evidence
of water retention, which can result in significant hyponatraemia.
 Contraindicated in patients with a history of severe arterial disease and
in children (Hyponatremia may lead to Fits)
- People with hemophilia should be registered at a comprehensive
care centre (CCC), which takes responsibility for their full medical
care, including social and psychological support.
• Complications
- Development of anti-factor VIII antibodies, which can make the
treatment ineffective. (25-30% of patients)
- Viral transmission (HIV, HBV, HCV) (Virtually eliminated).
Hemophilia B
• Factor IX deficiency, X-linked recessive
• Clinically indistinguishable from Hemophilia A
• Treatment: Factor IX concentrate, extended half-life recombinant
factor IX products once-weekly or two-weekly for prophylaxis.
Von-Willebrand Disease
• Mild bleeding disorder d/t vWF deficiency
• Age and sex: Young male
• Clinical features: bleeding
• Investigations: Bleeding time- prolong and Factor VIII- reduced,
Platelet count- normal.
Q. How to approach bleeding?
Three Questions should be asked:
1. Is there a generalized hemostatic defect?
• bleeding from multiple sites, spontaneous bleeding, and excessive bleeding
after injury
2. Is the defect inherited or accquired?
• A family history of a bleeding disorder
• Severe: become apparent in infancy, sometimes at the time of birth with
prolonged bleeding from the umbilical cord,
• Mild: later in life, for e.g. after surgery, childbirth, dental extractions or
trauma
3. Is the bleeding suggestive of a vascular/ platelet defect or a
coagulation defect?
• Vascular/Platelet defect
- Easy bruising and spontaneous small v/s bleeding
- Petechiae and purpura
- Mucosal bleeding: from mouth and nose
• Coagulation defect
- Bleeding after injury or surgery
- In more severe forms, haemarthroses and muscle haematomas.
Laboratory Investigations
• Full blood count & film: number and morphology of platelets and any blood
disorder, such as leukemia or lymphoma
• Bleeding time: measures platelet plug formation
• Prothrombin time: measures factors VII, X, V, prothrombin and fibrinogen
(normal: 11.5- 13.5 sec)
• APTT: measures factors XII, XI, IX, VIII, X, V, prothrombin and fibrinogen (normal:
26- 37 sec)
• Thrombin time: prolonged in Fibrinogen deficiency or at the presence of heparin
or FDPs (normal: 12-14 sec)
• Correction tests: used to differentiate prolonged times in the PT, APTT and TT
(Failure suggest the presence of coagulation inhibitors)
• Factor Assays
• Special tests of coagulation: estimation of fibrinogen and FDPs, platelet function
tests such as platelet aggregation, and platelet granule contents.
Thank You So Much!