Bleeding Disorders

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     6. 7. 8. 9. 10. 11.

Inherited vascular disorders: Hereditary hemorrhagic telangiectasia CT disorders- Ehler Danlos syndrome Acquired vascular disorders: Simple easy bruising Senile purpura Infections- measles, meningococci, rickettsiae Henoch- Schönlein purpura Scurvy 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

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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:

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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

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DIC

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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.

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Familial (genetic defect) & acquired forms (inhibitory antibodies stimulated by an infection)

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Fever, severe thrombocytopenia, microangiopathic hemolytic anemia, jaundice & neurological symptoms

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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

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E.coli & Shigella have a role & caspases are normal

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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

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Platelets are unstable if stored at 4oC

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Counts ↓ if stored for > 24 hrs

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Rx- platelet transfusions & FFP

Drugs These cause bleeding disorders due to: 

Suppression of the BM: cytotoxic drugs, ethanol, radiation, occasionallychloramphenicol, cotrimoxazole, idoxuridine, pencillamine, benzene, arsenicals

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

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Platelet aggregation: ristocetin, heparin

Idiopathic thrombocytopenic purpura Can be of two forms 2. Acute 3. Chronic

Chronic ITP 

F>M- 15 to 50 yrs

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Most common cause of bleeding disorder

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Mostly idiopathic

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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

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Removal by the macrophages in the spleen

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Lifespan is reduced from 7 days to a few hours

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Megakaryocyte mass and platelet turnover is ↑ to 5 time the normal

Clinical features 

Insidious onset

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Petechial hemorrhage, easy bruising, menorrhagia in women, mucosal bleeding

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Severity is lesser than in those with thrombocytopenia due to BM failure- due to circulating functionally superior younger platelets in ITP

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Tends to relapse and remit spontaneously

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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

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75% follow vaccination or infection such as chicken pox or infectious mononucleosis

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Due to nonspecific immunity

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Spontaneous remission in most

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5-10% become chronic

Diagnosis 

Platelet counts

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BM aspiration

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Counts over 30x109/l- no Rx

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Counts below 20x 109/l – steroids and/or IV Ig

Abnormal platelet function 

Abnormality in the functioning of the platelets

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May be primarily due to platelet dysfunction as in 

Bernard Soulier syndrome (Giant platelets, def. of Gp 1b [defective binding of vWF], thrombocytopenia) or

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Glanzman’s Thrombasthenia (Deficiency of membrane Gp IIb/IIIa complex (fibrinogen receptor)

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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

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Hemophilia B- Christmas disease- factor IX deficiency

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von Willebrand’s disease

Hemophilia A 

Most common inherited clotting factor deficiencies

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Sex linked inheritance

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33%-spontaneous mutation

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Others are missense or frameshift mutation or deletions

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Absence or low level of plasma factor VIII

Hemophilia A - Clinical features 

Infants- profuse hemorrhage, joint and soft tissue bleeds, excess bruising

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Prolonged bleeding after tooth extractions, spontaneous hematuria & GI bleeds

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Spontaneous intracerebral hemorrhages

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Hemophilic psuedotumors

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Complications- HIV, Hepatitis B & C

Lab findings 

Activated PTT are abnormal

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Factor VIII assays are abnormal

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Bleeding time & PT are normal

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DNA probes are used to detect carriers

Christmas disease 

Factor IX deficiency

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Incidence is 1/5th that of hemophilia A

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X-linked inherited disorder

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Factor IX infusions (longer biological half life)

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APTT & factor IX assays are abnormal

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Bleeding time & PT are normal

von Willebrand's disease 

Point mutation or deletions → abnormally functioning or reduced vWFautosomal dominant inheritance

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

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vWD is the most common inherited bleeding disorder

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Mucosal bleeds, excessive blood loss from superficial cuts & abrasions and operative & post traumatic hemorrhage

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Hemarthroses and muscle hematomas are rare

von Willebrand's disease - Lab findings 

Bleeding time is prolonged

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Factor VIII levels are low

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APTT-prolonged

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vWF- low

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Defective platelet aggregation

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Platelet counts are usually normal

Blood group antibodies 

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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.

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Mother is D negative, father is D positive, and fetus is D positive.

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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.

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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.

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Group O, Rh negative, uncross matched.

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Recipient may have an unexpected antibody.

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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 Platelets

Cryoprecipitate Factor VIII concentrate

Cryosupernatant

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 Blood components: a- Packed red cells. b- Platelets. c- Fresh frozen plasma.

b

c