Bleeding disorders

Dr. Mehzabin Ahmed

Causes
Abnormal bleeding may result from:
1) Vascular disorders
2) Platelet disorders
- Thrombocytopenia
- Defective platelet function
3) Defective coagulation
 Vascular disorders
 Inherited vascular disorders:
 Hereditary hemorrhagic telangiectasia
 CT disorders- Ehler Danlos syndrome
 Acquired vascular disorders:
6. Simple easy bruising
7. Senile purpura
8. Infections- measles, meningococci, rickettsiae
9. Henoch- Schönlein purpura
10. Scurvy
11. Steroid administration & Cushing’s syndrome
 Thrombocytopenia
Decreased platelet counts due to:
2. Failure of production of platelets
3. Increased destruction of the platelets
4. Abnormal distribution of the platelets
5. Dilutional loss

(normal counts are 150- 400 x 109/l & lifespan is 7 days)

 Failure in the platelet production
 Generalized BM failure as in leukemia, aplastic
anemia, MDS, myelofibrosis, multiple myeloma,
megaloblastic anemia, HIV infection, and
administration of cytotoxic drugs and radiotherapy

 Selective megakaryocytic depression may also result

due to the action of drugs, chemicals or viral infections
or rarely it is congenital
 Increased destruction of the platelets
 Immune mediated:
 Autoimmune (idiopathic) thrombocytopenic purpura-ITP
 Associated with diseases like SLE, CLL, lymphoma
 Infections like HIV, malaria- immune mediated damage
 Drug induced- drug dependent Abies+
 Heparin
 Post transfusion- Abies in the recipient against HPA-1a
 Feto-maternal alloimmune thrombocytopenia
 DIC
Increased destruction of the platelets (contd)
Thrombotic thrombocytopenic purpura
 Deficiency of a metalloprotease- caspase enzyme (cleaves von Willebrand
Factor)- ∴ inability to cleave vWF results in abnormally large multimers in the
plasma inducing platelet aggregation.
 Familial (genetic defect) & acquired forms (inhibitory antibodies stimulated by
an infection)
 Fever, severe thrombocytopenia, microangiopathic hemolytic anemia, jaundice
& neurological symptoms
 Rx: plasma exchange using FFP (fresh frozen plasma) or cryosupernatant.,
corticosteroids, vincristine, aspirin & immunosuppressants & No platelet
transfusion
HUS
 Similar to TTP but limited to kidneys in children
 E.coli & Shigella have a role & caspases are normal
 Renal dialysis & R of hypertension and convulsions & No platelet transfusion
Abnormal distribution of platelets
 Splenomegaly- platelet pooling- upto 90% are sequestered in the spleen

Dilutional loss
 Massive transfusion of stored blood (> 10 units/24 hr) to bleeding patients
 Platelets are unstable if stored at 4oC
 Counts ↓ if stored for > 24 hrs

 Rx- platelet transfusions & FFP

 Drugs
These cause bleeding disorders due to:
 Suppression of the BM:
cytotoxic drugs, ethanol, radiation, occasionally-
chloramphenicol, cotrimoxazole, idoxuridine, pencillamine,
benzene, arsenicals

 Immune mechanisms:
analgesics, antiinflammatory drugs, gold salts, rifampicin,
antimicrobials, sedatives and anticonvulsants, diuretics,
antidiabetics, digitoxin, quinine, methyl dopa, heparin

 Platelet aggregation: ristocetin, heparin

Idiopathic thrombocytopenic purpura
Can be of two forms
2. Acute
3. Chronic
 Chronic ITP
 F>M- 15 to 50 yrs
 Most common cause of bleeding disorder
 Mostly idiopathic
 Association with SLE, HIV, CLL, Hodgkin’s lymphoma, autoimmune
hemolytic anemia

Pathogenesis
 Autoantibodies- IgG type against the platelet Ag- glycoproteins IIb-IIIa or
Ib complex
 Removal by the macrophages in the spleen
 Lifespan is reduced from 7 days to a few hours
 Megakaryocyte mass and platelet turnover is ↑ to 5 time the normal
 Clinical features
 Insidious onset
 Petechial hemorrhage, easy bruising, menorrhagia in women, mucosal
bleeding
 Severity is lesser than in those with thrombocytopenia due to BM failure- due
to circulating functionally superior younger platelets in ITP
 Tends to relapse and remit spontaneously
 Splenomegaly +/-

Diagnosis
 Platelet counts – 10-50 x 109/l
 Hb concentration & WBC count is normal
 PS: ↓ platelets, often large
 BM: normal or ↑ megakaryocytes
 Specific antiglycoprotein GPIIb/IIIa or GPIb antibodies
Acute ITP
 Common in children
 75% follow vaccination or infection such as chicken pox or infectious
mononucleosis
 Due to nonspecific immunity
 Spontaneous remission in most
 5-10% become chronic

Diagnosis
 Platelet counts
 BM aspiration
 Counts over 30x109/l- no Rx
 Counts below 20x 109/l – steroids and/or IV Ig
Abnormal platelet function
 Abnormality in the functioning of the platelets
 May be primarily due to platelet dysfunction as in
 Bernard Soulier syndrome (Giant platelets, def. of Gp 1b
[defective binding of vWF], thrombocytopenia) or
 Glanzman’s Thrombasthenia (Deficiency of membrane Gp
IIb/IIIa complex (fibrinogen receptor)
 Gray platelet syndrome (α granule deficiency)
 Secondary to abnormalities in vWF function as in von Willebrand
disease
 Disorders of Coagulation
 Hemophilia A- factor VIII deficiency
 Hemophilia B- Christmas disease- factor IX
deficiency
 von Willebrand’s disease
 Hemophilia A
 Most common inherited clotting factor deficiencies
 Sex linked inheritance
 33%-spontaneous mutation
 Others are missense or frameshift mutation or
deletions
 Absence or low level of plasma factor VIII
 Hemophilia A - Clinical features
 Infants- profuse hemorrhage, joint and soft tissue bleeds, excess bruising
 Prolonged bleeding after tooth extractions, spontaneous hematuria & GI
bleeds
 Spontaneous intracerebral hemorrhages
 Hemophilic psuedotumors
 Complications- HIV, Hepatitis B & C

Lab findings
 Activated PTT are abnormal
 Factor VIII assays are abnormal
 Bleeding time & PT are normal
 DNA probes are used to detect carriers
 Christmas disease
 Factor IX deficiency
 Incidence is 1/5th that of hemophilia A
 X-linked inherited disorder
 Factor IX infusions (longer biological half life)
 APTT & factor IX assays are abnormal
 Bleeding time & PT are normal
 von Willebrand's disease
 Point mutation or deletions → abnormally functioning or reduced vWF-

autosomal dominant inheritance

 vWF- promotes platelet adhesion & is a carrier protein for factor VIII

 vWD is the most common inherited bleeding disorder

 Mucosal bleeds, excessive blood loss from superficial cuts & abrasions and

operative & post traumatic hemorrhage

 Hemarthroses and muscle hematomas are rare

von Willebrand's disease - Lab findings
 Bleeding time is prolonged
 Factor VIII levels are low
 APTT-prolonged
 vWF- low
 Defective platelet aggregation
 Platelet counts are usually normal
 Blood group antibodies
 Naturally occurring antibodies:
 Occur in the plasma of subjects who lack the corresponding antigen
and who have not been transfused or been pregnant.
 They are usually IgM reacting optimally at cold temp. (4°C).
Although they are also reactive at 37°C, they are still called cold
antibodies
 Immune antibodies:
 They develop in response to the introduction of red cells possessing
antigens which the subject lacks (by transfusion or by transplacental
passage during pregnancy).
 They are commonly IgG, although some IgM antibodies may also
develop (usually in the early phase of an immune response).
 They react optimally at 37ºC (warm antibodies).
 Only IgG antibodies are capable of transplacental passage from
mother to fetus.
 The most important immune antibody is the Rh antibody, anti-D.
Blood transfusion - ABO system:

 Antigens present on red cells are encoded by 3 allelic genes: A, B and O.

 The basic antigenic substance on RBC is H antigen.

 A and B genes encode for enzymes that modify the H antigen. O gene
does not produce any enzyme and hence does not transform the H
substance.

 A,B & H antigens are present in on most body cells including

WBC & platelets. They are also present in secretions &
body fluids e.g. plasma, saliva, semen and sweat (in people
possessing secretor genes).
ABO typing:
Rh system:

 Genes encoding the Rh system are Rh D and Rh CE.

 Rh D may be present or absent giving the Rh D+ / Rh D- phenotype

respectively.
 Rh blood group antigens are present only on RBCs.
 Rh positive means that the D antigen is present (85% on the population).
 Rh negative means that the D antigen is absent (15% of the population).
 The D antigen is highly immunogenic and Rh anti D antibodies are
immune and are responsible for most of the clinical problems associated
with the system.
 More than 80% of D negative persons receiving D positive blood are
expected to develop anti D.
Hemolytic diseases of the newborn (HDN):
 D antigen is the most important cause of HDN.
 Mother is D negative, father is D positive, and fetus is D positive.
 Fetus’ D positive RBCs enter mother’s circulation and mother makes anti-D
of IgG type which crosses the placenta.
 First pregnancy will pass unaffected.
 Maternal IgG crosses the placenta and affects the second D positive
pregnancy.
 Anti-D formation in mother prevented with Rhogam ( injection of Rh
immunoglobulin (RhIg) at 28 weeks of gestation and again after delivery).
Other blood group systems:
 Kell
 Duffy
 Kidd
 Lutheran
 Lewis
P
 MN
 Li

 Tests for antigens from these systems are not included in routine
blood typing, but they are commonly used in paternity
testing.
 Cross-matching and pre-transfusion tests:
 Steps taken to ensure that compatible blood is transfused to
recipient:

 From the patient:

 Determination of ABO and Rh group.
 Indirect Coomb’s test on the serum.

 From the donor:

 Selection of matching blood group and Rh.
Screening for infectious agents.
Cross-matching (patient's serum is added to the donor
cells and spun down to exclude agglutination).
Complications of blood transfusion:
 Hemolytic transfusion reactions (immediate or delayed):
 Immediate life threatening reactions may be caused by complement fixing
antibodies against ABO system, leading to intravascular hemolysis (clinical
features of major hemolytic transfusion reaction):
 Hemolytic shock phase: This may occur after only a few mLs of blood have
been transfused or up to 1-2 hr after the end of the transfusion (urticaria,
lumbar pain, headache, shortness of breath, vomiting, fall in BP…etc.)
 Oliguric phase: Renal tubular necrosis with acute renal failure.
 Diuretic phase: Fluid & electrolyte imbalance may occur during the recovery
from acute renal failure.
 Febrile reactions due to white cell antibodies (HLA).
 Allergic reactions (donor plasma).
 Circulatory overload.
 Iron overload.
 Sepsis.
 Viral transmission: HBV, HCV, HIV, CMV, and EBV.
 Other infections: Malaria, toxoplasmosis, syphilis.
Blood Used on Emergency Basis:
 Blood used on emergency basis:
 For a patient who is severely bleeding out.
 When the blood group of the patient is unknown.

 Group O, Rh negative, uncross matched.

 Recipient may have an unexpected antibody.

 After 5 min use ABO and Rh type specific blood.

Autologous donation and transfusion:
 Anxiety over AIDS and other infections, in addition to certain religious
beliefs, have increased the demand for auto transfusion.
 There are three ways of administering an autologous transfusion:

 Predeposit: Blood is taken from the potential recipient in the weeks

immediately prior to elective surgery.
 Haemodilution: Blood is removed immediately prior to surgery once
the patient has been anesthetized and then reinfused at the end of
the operation.
 Salvage: Blood lost during the operation is collected during heavy
blood loss and then reinfused.
Blood products:

 Collection of blood for donation: Employ aseptic technique,

and collect into plastic bags containing anticoagulant
(Citrate Phosphate Dextrose –CPD).

 Tests to be carried out : ABO grouping and Rh typing,

screening for infectious agents.

 Storage: 4-6 Co for up to 35 days.

The preparation of blood components from blood:

Whole blood

Cellular components Fresh plasma

Fresh frozen plasma

Red cells
White cells Cryoprecipitate Cryosupernatant
Platelets

Factor VIII concentrate

Albumin
Immunoglobulin
Other concentrates
Leucofiltration of blood is carried out by gravity through a depleting filter in
a closed system to remove WBCs. This helps to reduce the febrile transfusion
reactions and alloimmunization.
 a b c
Blood components:

a- Packed red cells.

b- Platelets.
c- Fresh frozen plasma.