Hemostasis Seminar Prepared by :- Mohammed Saadi Mohammed Musa Hussein Jassam Mahmoud Ahmed Internal Medicine College of Medicine - University of Kirkuk

1. HEMOSTASIS
Prepared by :-
• Mohammed Saadi
• Mohammed Musa
• Hussein Jassam
• Mahmoud Ahmed

2. Hemostasis mean prevention of blood loss is a physiological
arrest of haemorrhage at sites of vascular leakage.
It is a dynamic process in which the platelet and the blood vessel wall
play key roles.
Platelets become activated upon adhesion to (vWF) and collagen in the
exposed subendothelium after injury

3. The platelet
• Bone morrow  megakaryocyte platelet which regulated by thrombopoietin
(TPO)
• Decrease platelet count and megakaryocyte mass will increases the level
of TPO which then stimulates platelet production.
• Platelets life span of 7 to 10 days
• Normal vascular endothelium prevent thrombosis by inhibiting platelet function

4. • When vascular endothelium is injured, platelets adhere to the exposed intimal
surface primarily through vWF
• Platelet released granules promote platelet aggregation and blood clot
formation
• additional platelets are recruited to the site of injury, leading to the formation of
an occlusive platelet thrombus.
• The platelet plug is stabilized by the fibrin mesh that develops simultaneously
as the product of the coagulation cascade.

7. FIBRINOLYSIS
PLASMINOGEN PLASMIN
FIBRIN FDP,D-DIMERS
INHIBITORY EFFECTS ON CLOT
FORMATION
PLASMINOGEN
ACTIVATORS
KALLIKREIN
XIIa PLASMINOGEN
ACTIVATORS
t-PA
UROKINASE
STREPTOKINASE

8. THE HISTORY
SHOULD DETERMINE:
 The site or sites of bleeding, the severity and
duration of hemorrhage, and the age at onset.
 Was the bleeding spontaneous, or did it occur
after trauma?
 Was there a previous personal or family history of
similar problems?
 If a child or adolescent has had surgery that
affects the mucosal surfaces, such as a
tonsillectomy or major dental extractions, the
absence of bleeding usually rules out a
hereditary bleeding disorder

9. PHYSICAL EXAMINATION
 The P/E should focus on whether bleeding symptoms are associated primarily with
the mucous membranes or skin (mucocutaneous bleeding) or with the
muscles and joints(deep bleeding).
 The examination should determine the presence
of petechiae, ecchymoses,
hematomas, hemarthroses, or mucous membrane bleeding.
 Patients with defects in platelet-blood vessel wall interaction (VWD or platelet
function defects) usually have mucocutaneous bleeding.
 Individuals with a clotting factor deficiency of factor VIII or IX (hemophilia A
or B) have symptoms of deep bleeding into muscles and joints.
 Individuals with disorders of the collagen matrix and vessel wall may have loose
joints and lax skin associated with easy bruising (Ehlers-Danlos syndrome).

10. LABORATORY
INVESTIGATIONS TESTS FOR COAGULATION
FACTORS
I. Prothrombin Time(PT)
II. Activated Partial Thromboplastin
Time(APTT)
III. Thrombin Time(TT)
IV. Fibrinogen assay
 TESTS FOR
PLATELET
I. Platelet count
II. Bleeding Time(BT)

11. Significance
 Reflects overall activity of the Extrinsic Pathway.
 Most sensitive to changes in Factor V,VII,X.
 Lesser to Factor I & II.
Normal Range
10-12 seconds
PROTHROMBIN TIME
(PT)

12. INTERPRETATION
Causes of prolonged PT:
1. Deficiency of Factor VII,X,V,II,I
2. Vit K deficiency
3. Liver disease esp.Obstructive Jaundice
4. Oral anticoagulants
5. DIC

13. ACTIVATED PARTIAL THROMBOPLASTIN TIME (APTT)
Significance
 Reflects efficiency of Intrinsic Pathway.
 Sensitive to changes in Factor VIII,IX,XI,XII.
 Also sensitive to heparin & circulating anticoagulants.
Normal range
26 to 40 seconds.

14. INTERPRETATION
Causes of prolongedAPTT:
1. Deficiency of Factor VIII(Hemophilia A).
2. Deficiency of Factor IX(Hemophilia B).
3. DIC.
4. Heparin therapy.
5. Circulating anticoagulants.
6. Liver disease.
7. Massive transfusion of plasma depleted stored
blood.

15. THROMBIN TIME (TT)
Significance
Asses the final step of coagulation i.e. conversion of fibrinogen to fibrin in
presence of thrombin.
Bypasses Extrinsic & Intrinsic pathway.
Normal range
A patient’s TT should be within 2 s of the control
(i.e. 15–19 sec). Times of 20 s and longer are definitely abnormal.

16. INTERPRETATION
Causes of prolonged TT:
1. Disorders of fibrinogen-
Afibrinogenaemia.
Hypofibrinogenaemia.
Dysfibrinogenaemia.
2. Presence of FDP- DIC or Liver disease.
3. Unfractioned heparin therapy.
4. Hypoalbuminaemia.
5. Paraproteinaemia.
.

17. FIBRINOGEN
ASSAY
Usually done by CLAUSS TECHNIQUE.
Normal range
1.8 to 3.6 g/l
Interpretation
Sensitive to inherited Dysfibrinogenaemia.
 Insensitive to Heparin unless the level is very high(>0.8µ/µl).
 High level of FDP(>190µg/ml)may also interfare with the result.

18. PLATELET COUNT & BLEEDING
TIMEPlatelet count must be done in a suspected bleeding disorder. PBS must be examined for
size & staining properties of plt.
BLEEDING TIME(BT)
Significance
Assess Primary Hemostatic defect(vessel wall or platelet). Dependent on adequate
functioning of plt. & Bl.Vs.
Methods
I. Ivy’s
II. Duke’s-not recommended.
III. Template
Range
• Ivy’s method: 2 to 7 mins.
• Template method: 2.5 to 9.5 mins.

19. INTERPRETATION
Causes of prolonged BT:
I. THROMBOCYTOPENIA.
II. VWD.
III. PLATLET FUNCTION DISORDER.
IV. DISORDERSOF BLOOD VESSEL.

20. DIAGNOSIS OF VESSEL WALL
DISORDER LABORATORY TESTS: TPC,PT, APTT,TT are usually normal.
The only test of any use is BT. BT may be normal or
increased.
HESS` CAPILLARY FRAGILITY TEST:
• Cuff is wrapped in upper arm and pressure is maintained midway b/w systolic and
diastolic BP for 15 minutes.
• 4 cm below the elbow joint, a circle of 2.5 cm diameter is drawn on the anterior aspect
of forearm.
• Upto 10 new hemorrhagic spots are normal.
• But >20 new spots are always pathological.
• This is positive in increased capillary fragility, ITP.

21. Disorder of primary
haemostasis
DISORDER OF VESSEL WALL

22. HERIDITORY HAEMORRHAGIC TELENGECTASIA
(HHT)
• Is dominantly inherited condition characterised by abnormalities of
vascular modelling.
• Telangiectasia and small aneurysms occur on the fingertips, on the face ,
in the nasal passages, on the tongue, in the lung and in the GI tract.

23. • Many patients develop larger pulmonary arteriovenous malformations
that cause arterial hypoxaemia and are associated with stroke and
cerebral abscess due to paradoxical embolism; these should be
treated by percutaneous embolisation.
• Patients present with recurrent bleeds (particularly epistaxis)or with
iron deficiency due to occult GI bleeding.

25. Treatment of HHT
• Iron therapy
• Local cautery
• Laser therapy to prevent lesions from bleeding.

26. Ehlers danlos disease
• is a rare autosomal dominant disorder caused by defect in type 3 collagen
which result in fragile blood vessel and organ membranes leading to bleeding
and organ rupture.
• Classical joint hyeper mobility is often limited in this form of the disease but
skin changes and and facial appearance are typical.
• The diagnosis should be considered when there is a history of bleeding but
normal laboratory tests.

28. Scurvy
• Vitamin c deficiency affects the normal synthesis of collagen and
results in bleeding disorder
• characterized by perifollicular and petechial haemorrhage ,brusing
and subperiosteal bleeding.
• The key to diagnosis is the dietary history.

30. Platlet disorder
# Thrombocytopenia
• Its result from one or more of three process :
- decrease bone morrow production
- sequestration usually occur with enlarged spleen
- increase platlet destruction
• The common acquired disorder is iatrogenic (Aspirin , Clopidogrel )

31. • The key step in evaluation of patient with thrombocytopenia is to review the
prephral blood smear to rule out psoudothrombocytopenia which result from
lab error , because of platlet agglutination via anti bodies (IgG,IgM,IgA)
• When blood collected in EDTA tube , if you find low platlet count blood
smear should be evaluated again by either fresh blood sample or collect the
sample in heparin or sodium citrate tube

32. Normal prephral blood film Psoudothrombocytopenia
(platlet clumping )

33. CAUSES of thrombocytopenia
• A reduced platelet count may arise by one of two mechanisms:
• decreased or abnormal production (bone marrow failure and hereditary
thrombocytopathies)
• increased consumption following release into the circulation (immune-mediated, DIC
or sequestration).

34. Decreased production:
• Marrow hypoplasia
• Childhood bone marrow failure syndromes, e.g. Fanconi’s anaemia, dyskeratosis congenita,
amegakaryocytic thrombocytopenia
• Idiopathic aplastic anaemia
• Drug-induced: cytotoxics, antimetabolites
• Transfusion-associated graft-versus-host disease
• Marrow infiltration
• Leukaemia .
• Myeloma
• Carcinoma (rare)
• Myelofibrosis
• Osteopetrosis
• Lysosomal storage disorders, e.g. Gaucher’s disease

35. Decreased production:
• Haematinic deficiency
• Vitamin B12 and/or folate deficiency
• Familial (macro-)thrombocytopathies
• Myosin heavy chain abnormalities, e.g. Alport’s syndrome, Fechtner’s syndrome, May–Hegglin
anomaly
• Bernard–Soulier syndrome
• Montreal platelet syndrome
• Wiskott–Aldrich syndrome (small platelets)
• Mediterranean macrothrombocytopathy

36. Increased consumption:
• Immune mechanisms
• Idiopathic thrombocytopenic purpura
• Neonatal alloimmune thrombocytopenia
• Post-transfusion purpura
• Drug-associated, especially quinine, vancomycin and heparin
• Coagulation activation
• Disseminated intravascular coagulation
• Mechanical pooling
• Hypersplenism

37. Increased consumption:
• Thrombotic microangiopathies
• Haemolytic uraemic syndrome (HUS) and atypical HUS
• Liver disease
• Thrombotic thrombocytopenic purpura
• Pre-eclampsia
• Others
• Gestational thrombocytopenia
• Type 2B von Willebrand disease

38. Clinical features & Lab dx
• if platelet count < 20 x 109/L  spontaneous bleeding
• If platelet < 10 x109/L  retinal & intracranial hg(fetal )
• Purpura & spontaneous bruising are characteristic
• Blood film is single useful test
• B.morrow  ↑megakaryocyte

39. Treatment
• Depend on the cause
• Platelet transfusion if:
• B.morrow failure
• profound ↓ of platelet count
• serious bleeding
• This provide temporary relieve because platelet survival is few days only

40. Idiopathic Thrombocytopenic Purpura (ITP)
• It is autoimmune mediated destruction of platelet with inhibition of platelet release
from megakaryocyte.
• In children it is acute self limiting disease following an infection.
• In adult it is secondary and more chronic, caused by: autoimmune: SLE, infection:
HIV, hepatitis C, B-cell malignancy.

41. Clinical presentation
• Mucocutanous bleeding (Oral mucosa, GIT, heavy menstrual bleeding)
• Ecchymosis, petechiae
• Very low platelet count
• Otherwise normal peripheral blood smear
• Wet purpura (blood blister in mouth)
• Retinal hemorrhage
• rarely life threatening ( if CNS involved )

43. Wet purpura

44. Laboratory finding :
• Very low platelet count & peripheral smear shows large platelets with normal morphology.
• Serology for autoantibody : not helpful because of low specificity & sensitivity
• Bone morrow ex : if age>60 , signs not explained by ITP or no response to initial therapy.
• Test searching for secondary cause (HIV , hepatitis C , SLE
• S.protein electrophoresis and Ig level for Hypogammaglobulinemia
• Coombs test : if anemia present to exclude combined autoimmune hemolytic anemia (Evans
syndrome)

45. Treatment :
if sever thrombocytopenia
without bleeding symptoms:
treated as outpatient with single agent of :
• prednisolone 1 mg/kg daily
• iv. Anti-D 50-75 µg/kg
• IVIg 2 g/kg as total given in divided doses with in 2 - 5 days has more efficacy in
post splenectomized patient

46. with bleeding symptoms
Admission to hospital with combined therapy :
• high dose glucocorticoid + IVIgG + immune suppressive drug (rituximab)
• Platelet transfusion in case of life threatening bleeding
• in treatment of refractory type anti CD20 antibody show efficacy, also Romiplostim & Eltrombopag are
useful.
• Relapses should be treated by re-introducing corticosteroids. If a patient has two relapses, or primary
refractory disease, splenectomy is considered .
• Splenectomy produces complete remission in about 70% of patients and improvement in a further 20-
25%, so that following splenectomy only 5-10% of patients require further medical therapy.
• spleenectomy if relaps after tapering of steroid but if bleeding persist  give rituximab, ciclosporin
• vaccination against (pneumococcus , H.influanze, meningococcus(

47. Thrombotic Thrombocytopenic Purpura (TTP)
• Pathogenesis of inherited and idiopathic type is : deficiency of /or antibodies to
metalloprotease ADAMTS13 that cleavs vWF
• Can be associated with drugs, autoimmune disease, infection (E.coli , HIV) and
pregnancy
Microangiopathic
hemolytic anemia
Thrombocytopenia Renal
failure
Neurological
finding
Fever

48. Normally the ultra –high-molecular weight multimeres of vWF produced by endothelial cell are
processed into smaller multimeres by ADAMTS13 while in TTP the activity of protease inhibited
and the ultra-high-molecular weight multimeres of vWF intiate platlet aggregation and thrombosis

49. Investigations of TTP :
1-PT ,PTT & fibrinogen are typically normal, although fibrin split products may be
elevated.
2-decrease haptoglobin
3- increase lactate dehydrogenase and indirect bilirubin
4- increase reticulocyte count
5- prepheral blood smear : schistocyte , polychromasia , neucleated RBCs
6- -ve coombs test
7- may be microscopic haematuria & proteinurea

50. Treatment of TTP :
• Plasma exchenge (FFP) is the mainstay of treatment, Should continued until
platlet count become normal and sign of hemolysis improved at least 2 day
• Glucocorticoid as adjunctive therapy
• Immune modulatory therapy for refractory cases: (vincristine, cyclophosphamide)
• Splenectomy

51. Coagulation disorder
• GENITIC :
- Hemophilia A & B
- von-willebrand disease
- factor xi defiency
• ACQUIRED :
- DIC
- vit k defiency
- liver dsease
- renal disease
- Acquired hemophilia A

52. HAEMOPHILIA – A
• The most common congenital coagulation disorder.
• Characterized by a reduction in factor VIII.
• The factor VIII protected from proteolysis by binding to VWF
• It is inherited as an X-linked recessive disorder and patients are therefore
male. And daughters of haemophiliacs are carriers.
• If a carrier has a son, he will have a 50% chance of having haemophilia, and
a daughter will have a 50% chance of being a carrier.

54. ISTH criteria for severity of hemophilia

55. Clinical features
• Dx made after the age of 6 months, when babies become more
mobile and first experience bruising or haemarthrosis.
• Features of haemophilia A are related to the plasma factor VIII level

56. • Severe haemophilia experience recurrent haemarthroses in large joints
synovitis & secondary osteoarthrosis.
• Spontaneous bleeding can occur at almost any site ( skin, muscle, joint ) if < 1%
of normal factor VIII level.
• Intracranial haemorrhage is often life threatening.

57. Hematoma

58. Hemophilic arthropathy

59. Prominent damage of knee & elbow joint

61. Dx of hemophilia A:
• Platelet count  normal
• PTT  prolonged
• PT  normal
• Thrombin time  normal
• Bleeding time  normal
• Factor VIII assay  reduced
• Anemia (IDA)  bleeding

62. Management
• In sever haemophilia, bleeding episodes should be treated early with
i.v.factor VIII concentrate.
• Resting of bleeding site by either bed rest or splint reduces continuing
bleeding .
• Once bleeding has settled, the patient should be mobilised and
physiotherapy used to restore strength of surrounding muscles.

63. • In individuals with mild & moderate haemophilia A, vasopressin receptor
agonist Desmopressin can be used to increase factor VIII levels & vWF. The dose
is 0.3 µg/kg given i.v or subcutaneously .
• Same effects can be achieved by intra nasal administration of 300µg.
• In addition to to tx (on demand )for bleeding ,factor VIII can be administered 2 or 3
times/week as prophylaxis to prevent bleeding in sever haemophilia.
• Cryopricipitate is inriched with FVIII protein(each contains 80 IU of FVIII) can be
used.

64. Complications of therapy
(1) Before 1985 concentrates were not virally inactivated. As a result, many patients
treated became infected with hepatitis B, hepatitis C and HIV.
• Viral inactivation of blood products eradicated this risk
(2) Development of anti-factor VIII antibodies, which arise in about 20% of severe
haemophiliacs .Such antibodies rapidly neutralize therapeutic infusions ,making
treatment relatively ineffective.
• Infusion of factor VIIa may stop bleeding.

65. HAEMOPHILIA - B
(CHRISTMAS DISEAS)
• This is caused by deficiency of factor IX and is also an X-linked condition.
• The disorder is clinically indistinguishable from haemophilia A but is less
common
• Treatment is with factor IX concentrate

66. Von Willebrand Disease
The most common autosomal dominant inherited bleeding disorder due to
deficiency of vwf which is synthesised by endothelial cell and megakaryocyte
The vWF has 2 major role :
1- Adhesion of platlet to the exposed subenothelium
2- Binding protein for FVIII resulting significant prolongation of FVIII half live in
circulation

68. Type and lab feature for each type
The most common type is type 1 (80% of cases )

69. Clinical feature of vWD
• mucosal bleeding
• postoperative bleeding
• uncommon in infant
• excessive bruising in unusual traumatized area
• epistaxis ,
• Menorrhagia
• Hemearthrosis unlikly

73. Labrotary finding
• platelet  normal
• bleeding time  prolonged
• PT  normal
• PTT  prolonged
• thrombin time  normal
• Factor VIII & VWF  reduced

74. Treatment
• TYPE 1, 2A,2M VWD
• Desmopressin i.v (30minute) ) (0.3 ugkg) or nasal spray (2hour
side effect of Desmopressin :hyponatremia
fluid restriction advised for 24h after each dose
• TYPE 3 Vwf replacement
• Antifibrinolytic drug (tranexamic acid ,a-aminocaproic acid ) for prevention or stopping mucosal
bleeding
• Cryoprecipitate
• Desmopressen
• Factor VIII concentrate

75. Disseminated intravascular
coagulation (DIC)
• Is a clinicopathologic syndrome characterized by widespread intravascular
fibrin formation in response to excessive blood protease activity that
overcomes the natural anticoagulant mechanisms.
• Result from endothilial damage due to : toxaemia or septicemia by activating
extrinsic pathway of coagulation cascade

77. The most common causes
• Bacterial sepsis (E.coli , Malaria, Neisseria , Streptococcus )
• Obstetric causes : abruptio placentae or with amniotic fluid embolism, pre-eclampsia
• Trauma, particularly to the brain
• Burns
• Exposure of blood to phospholipids from damaged tissue
• Hemolysis
• Endothelial damage
• Malignancy: lung, pancreas, prostate
• Snake venom

78. Clinical feature
• bleeding from oozing from venipuncture sites,
• petechiae, and ecchymoses
• severe hemorrhage from the gastrointestinal tract or lung or CNS
• the bleeding symptoms are discrete and restricted to skin
or mucosal surfaces.

79. • The hypercoagulability of DIC manifests as the occlusion of vessels
in the microcirculation and resulting organ failure.
• Thrombosis of large vessels and cerebral embolism can also occur
• Hemodynamic complications and shock
• The mortality rate ranges from 30 to >80% depending on the
underlying disease, the severity of the DIC, and the age of the patient.

82. Laboratory finding
• Prolongation of PT and/oraPTT, due to factor V and fibrinogen deficiency)
• Platelet counts ≤100,000/ìL3 or a rapid decline in platelet numbers,
• Presence of schistocytes (fragmented red cells) in the blood smear,
• Elevated levels of FDP it is most sensitive test for DIC
• The D -dimer test is more specific for detection of fibrin—but not fibrinogen—
degradation products and indicates that the cross-linked
• Fibrin has been digested by plasmin.
• Thrombocytopenia, low fibrinogen concentration

83. ISTH scoring system for diagnosis of DIC:
• Presence of an associated disorder
• Platelets: >100 = 0 , <100 = 1 , <50 = 2
• Elevated fibrin degradation products: No increase = 0 , Moderate = 2 , Strong = 3
• Prolonged prothrombin time: < 3 s = 0 , > 3 s but < 6 s = 1 , > 6 s = 2
• Fibrinogen: > 1 g/L = 0 , < 1 g/L = 1
• Total score: ≥ 5 = Compatible with overt DIC
< 5 = Repeat monitoring over 1-2 days
(ISTH = International Society for Thrombosis and Haemostasis)

84. Chronic DIC
• Low-grade, compensated DIC can occur in clinical situations including giant hemangioma,
metastatic carcinoma, or the dead fetus syndrome.
• Plasma levels of FDP or D -dimers are elevated. aPTT, PT, and fibrinogen values are
within the normal range or high.
• Mild thrombocytopenia or normal platelet counts are also common findings.
• Red cell fragmentation is often detected but at a lower degree than in acute DIC.

86. DDX OF DIC:
1- severe liver disease are at risk for bleeding an manifest laboratory features
including thrombocytopenia (due to platelet sequestration, portal hypertension, or
hypersplenism), decreased synthesis of coagulation factors and natural
anticoagulants, and elevated levels of FDP due to reduced hepatic clearance.
2- thrombotic thrombocytopenic purpura present an acute clinical onset of illness
accompanied by thrombocytopenia, red cell , fragmentation and multiorgan failure.

88. Vitamin K Deficiency
• Vitamin K–dependent proteins are a heterogenous group, including clotting factor
proteins and also Proteins found in bone, lung, kidney, and placenta
• The amount of vitamin K in the diet is often limiting for the carboxylation reaction;
thus, recycling of the vitamin K is essential to maintain normal levels of vitamin K–
dependent proteins.

89. • In adults, low dietary intake alone is seldom reason for severe vitamin K deficiency but may
become common in association with the use of broad spectrum antibiotics
• Neonatal vitamin K deficiency and the resulting hemorrhagic disease of the newborn have
been almost entirely eliminated by routine administration of vitamin K to all neonates
• Prolongation of PT values is the most common and earliest finding in vitamin K–deficient
patients due to reduction in prothrombin, FVII, FIX, and FX levels. FVII has the shortest
half-life among these factors that can prolong the PT before changes in the aPTt.

91. Management:
• Parenteral administration of vitamin K at a total dose of 10 mg is sufficient to restore normal levels of
clotting factor within 8–10 h replacement with FFP or PCC is required
• The reversal of excessive anticoagulant therapy with warfarin or warfarin-like drugs can be achieved
by minimal doses of vitamin K
• In patients with life-threatening bleeds, the use of recombinant factor VIIa in nonhemophilia patients
on anticoagulant therapy has been shown to be effective at restoring hemostasis rapidly

92. Acquired Inhibitors of Coagulation
Factors:
• An acquired inhibitor is an immune-mediated disease characterized by the
presence of an autoantibody against a specific clotting factor.
• FVIII is the most common target of antibody formation, but inhibitors to
prothrombin,FV, FIX, FX, and FXI are also reported.
• The disease occurs predominantly in older adults (median age of 60 years) but
occasionally in pregnant or postpartum women with no previous history of
bleeding..

93. • In 50% of the patients with inhibitors, no underlying disease is identified at the time
of diagnosis.
• In the remaining, the causes are :
autoimmune diseases, malignancies, dermatologic diseases , and pregnancy.
• Bleeding episodes occur commonly in soft tissues, in the gastrointestinal or urinary
tracts, and on the skin. Retroperitoneal hemorrhages and other life-threatening
bleeding may appear suddenly.

94. • The overall mortality rate in untreated patients ranges from 8 to 22%, and most
deaths occur within the first few weeks after presentation.
• The diagnosis is based on the prolonged aPTT with normal PT andTT.Clinical
features of these antibodies include bleeding from a primary hemostastatic defect or
coagulopathy that sometimes can be life threatining..
• The most common autoantibodies that affect clotting factor activity and lead to a
bleeding disorder are directed against, and interfere with, the activity of factor VIII, a
condition also called acquired hemophilia A

96. Liver disease
In sever liver disease causes of bleeding is :
• ↓ synthesis of factor II , VII , IX , X, fibrinogen
• In DIC reduced clearance of plasminogen activator
• Thrombocytopenia secondary to Hypersplenism
• Cholestatic jaundice reduce vit k absorption

97. Renal failure
• Hemorrhagic state is proportional to plasma urea level
• GIT hemorrhage is common
Causes are :
- anemia
- mild thrombocytopenia
- low molecular wt waste product

98. Treatment
• Dialysis
• Platelet concentrate
• RBC transfusion
• VWF concentrate & Desmopressin may be helpful

99. Antiplatelet Drugs:
Aspirin:
The most widely used antiplatelet agent worldwide is aspirin. As a cheap and effective antiplatelet drug, it
serves as the foundation of most antiplatelet strategies.
Advantages:
1-secondary prevention of ischaemic attack, ischaemic stroke and myocardial infarction.
2-prevention of ischaemic events in patients with angina pectoris.
3-prevention of coronary artery bypass graft occlusion.
Disadvantages:
1-risk of gastrointestinal adverse events.
2-allergic reactions.
3-aspirin resistance.
4-the irreversible platelet inhibition.

100. Thienopyridines:
The thienopyridines include ticlopidine, clopidogrel,and prasugrel are used in the treatment
and prevention of ACS and prevention of thromboembolic events.
Advantages;
1-secondary prevention of ischaemic complications after myocardial infarction,ischaemic
stroke and established peripheral arterial disease.
2-secondary prevention of ischaemic complications in patients with acute coronary
syndome.
Disadvanteges:
1-clopidogrel bind irreversibly to platelets.
2-clopidogrel dresistance.
3- clopidogrel is only slightly more effective than aspisin

101. Dipyridamole:
Dipyridamole is a relatively weak antiplatelet agent on its own, but an extended-release formulation of
dipyridamole combined with low-dose aspirin, a preparation known as Aggrenox.
Advantages:
is used for prevention of stroke in patients with transient ischemic attacks.
Diadvantages:
1-not very effective antithrombotic drug.
2-Dipyridamole has a vasodilatory effects, it must be used
with caution in patients with coronary artery disease.
Gastrointestinal complaints, headache, facial flushing,
dizziness, and hypotension can also occur. These
symptoms often subside with continued use of the drug.

102. GLY COPROTEIN IIb/IIIa Receptor Antagonists:
The three agents in this class are Abciximab, Eptifibatide, and Tirofiban.
Advantages:
1-Abciximab and eptifibatide are used in patients undergoing percutaneous
coronary interventions, particularly those with acute MI.
2-Tirofiban is used in high-risk patients with unstable angina.
Eptifibatide also can be used for this indication.
Disadvantages:
1- bleeding, thrombocytopenia is the most serious complication.
2-can only be administered by intravenous infusion and are
complicated to manufacture.

103. Anticoagulants:
• There are both parenteral and oral anticoagulants. Currently available parenteral
anticoagulants include heparin, low-molecular-weight heparin (LMWH), and
fondaparinux, a synthetic pentasaccharide. The only available oral anticoagulants
are the vitamin K antagonists, of which warfarin is the agent most often used.
Advantages:
1-To reduce the coagulability of blood.
2- prevent thrombus formation.

104. Parenteral Anticoagulants:
Heparin
• Heparin is a sulfated polysaccharide and is isolated from mammalian tissues rich in mast cells.
• The most common side effect of heparin is bleeding. heparin may also cause thrombocytopenia,
hypersensitivity, alopecia and osteoporosis.
LMWH
• Consisting of smaller fragments of heparin, LMWH is prepared from unfractionated heparin by
controlled enzymatic or chemical depolymerization.
• The major complication of LMWH is bleeding. HIT and osteoporosis are less common with LMWH
than with unfractionated heparin.

105. Fondaparinux
• A synthetic analogue of the antithrombin-binding pentasaccharide sequence,
fondaparinux differs from LMWH in several ways.
• Fondaparinux is licensed for thromboprophylaxis in general medical or surgical
patients and in high-risk orthopedic patients and as an alternative to heparin or
LMWH for initial treatment of patients with established VTE

106. Parenteral direct thrombin inhibitor
• Heparin and LMWH are indirect inhibitors of thrombin because their activity is
mediated by antithrombin.
• In contrast, direct thrombin inhibitors do not require a plasma cofactor; instead,
these agents bind directly to thrombin and block its interaction with its substrates.
Lepirudin
Argatroban
Bivalirudin

107. Oral Anticoagulants
Warfarin
• A water-soluble vitamin K antagonist initially developedas a rodenticide, warfarin is the coumarin
derivative.
• it is used in :
• prophylaxis and treatment of VTE.
• prophylaxis of emobilisation in AF.
• prophylaxis of thrombus formation in patients with a prosthetic heart valve.
• Like all anticoagulants, the major side effect of warfarin is bleeding.
• A rare complication is skin necrosis. Warfarin crosses the placenta and can cause fetal
abnormalities. Consequently, warfarin should not be used during pregnancy

108. Fibrinolytic Drugs
• act as thrombolytics by activating plasminogen to form plasmin wich breaks down
fibrin within a thrombus.they are indicated in the treatment of acute MI,serious
pulmonary embolus and acute stoke.
• all carry a serious risk of causing serious haemorrhage and are containdicated in
vulnerable patients.

109. Streptokinase:
a proteolytic enzyme produced by hemolytic streptococci that promotes the
dissolution of blood clots by activating plasminogen to produce plasmin
Anistreplase:
a thrombolytic complex of plasminogen and streptokinase used especially to treat
heart attack and to lyse thrombi in coronary arteries
Urokinase:
an enzyme that is produced by the kidney and found in urine, that activates
plasminogen, and that is used therapeutically to dissolve blood clots

110. Alteplase
a recombinant form of tissue plasminogen activator that is used to prevent damage to
heart muscle following a heart attack and to reduce neurological damage following
ischemic stroke
Reteplase
a recombinant form of tissue plasminogen activator used intravenously as a
thrombolytic agent in treatment of myocardial infarction.

111. References: