4

BLEEDING DISORDERS

Haemostasis
Is the physiological arrest of hemorrhage at sites of vascular leakage. There are mainly 5 systems which interact together to ensure hemostasis, namely : 1. Coagulation system. 2. Natural Coagulation inhibitors. 3. Vascular factors. 4. Platelets. 5. Fibrinolytic system.

Coagulation screening tests

Situations in which tests may be abnormal
Normal range
Investigation
Thrombocytopenia

Platelet count

Thrombocytopenia
<8 mins
Bleeding time
Abnormal platelet function

von Willebrand disease

Vascular and connective tissue abnormalities

Deficiencies of factors II, V, VII or XSevere fibrinogen deficiency ,warfarin therapy

9-12 secs
Prothrombin time (PT)
Deficiencies of factors II, V, VIII, IX, X, XI, XIISevere fibrinogen deficiencyUnfractionated heparin therapyAntibodies against clotting factorsLupus anticoagulant
26-36secs
Activated partial thromboplastin time (APTT)
Hypofibrinogenaemia, e.g. liver failure, disseminated intravascular coagulation
1.5-4 g/L
Fibrinogen concentration

RESPONSE TO VASCULAR INJURY

Vessel
INJURY
Leakage
Constriction
Platelet Plug
Fibrin reinforced Platelet Plug
Secondary hemostasis
Remodelling & Fibrinolysis
Return to normal
Primary hemostasis

Coagulation pathways

APTT Intrinsic +Common
Activated Partial Thromboplastin Time

PT extrinsic +Common

Prothrombin Time

T.T.

Thrombin Time15–18 s


DISORDERS OF PRIMARY HAEMOSTASIS The initial formation of the platelet plug ( also known as 'primary haemostasis') may fail in thrombocytopenia, von Willebrand disease , and also in platelet function disorders and diseases affecting the vessel wall. VESSEL WALL ABNORMALITIES Vessel wall abnormalities may be: congenital, such as hereditary haemorrhagic telangiectasia acquired, as in a vasculitis or scurvy.

Hereditary haemorrhagic telangiectasia: HHT is a dominantly inherited condition caused by mutations in the genes. Telangiectasia and small aneurysms are found on the fingertips, face and tongue, and in the nasal passages, lung and gastrointestinal tract. A significant proportion of these patients develop larger pulmonary arteriovenous malformations (PAVMs) that cause arterial hypoxaemia due to a right-to-left shunt. These predispose to paradoxical embolism, resulting in stroke or cerebral abscess.

Patients present either with recurrent bleeds, particularly epistaxis, or with iron deficiency due to occult gastrointestinal bleeding. Treatment can be difficult because of the multiple bleeding points but regular iron therapy often allows the marrow to compensate for blood loss. Local cautery or laser therapy may prevent single lesions from bleeding.


Ehlers-Danlos disease: Vascular Ehlers-Danlos syndrome (type 4) is a rare autosomal dominant disorder (1 in 100 000) caused by a defect in type 3 collagen which results in fragile blood vessels and organ membranes, leading to bleeding and organ rupture. Classical joint hypermobility is often limited in this form of the disease but skin changes and facial appearance are typical. The diagnosis should be considered when there is a history of bleeding but normal laboratory tests. Scurvy: Vitamin C deficiency affects the normal synthesis of collagen and results in a bleeding disorder characterised by perifollicular and petechial haemorrhage, bruising and subperiosteal bleeding. The key to diagnosis is the dietary history.

PLATELET DISORDERS: Bleeding may result from thrombocytopenia or from congenital or acquired abnormalities of platelet function. The most common acquired disorders are iatrogenic, resulting from the use of aspirin, clopidogrel, dipyridamole and the IIb/IIIa inhibitors to prevent arterial thrombosis . Inherited platelet function abnormalities are relatively rare. Congenital abnormalities may be due to deficiency of the membrane glycoproteins, e.g. Glanzmann's thrombasthenia (IIb/IIIa) or Bernard-Soulier disease (Ib), or due to the presence of defective platelet granules, e.g. a deficiency of dense (delta) granules giving rise to storage pool disorders.

Thrombocytopenia (low platelet count): 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, disseminated intravascular coagulation (DIC) or sequestration).

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

Haematinic deficiency Vitamin B12 and/or folate deficiency Familial (macro-)thrombocytopathies Myosin heavy chain abnormalities, e.g. Alport's syndrome, Fechner's syndrome Bernard Soulier disease Montreal platelet syndrome Wiskott-Aldrich syndrome (small platelets)

Increased consumption of platelets Immune mechanisms Idiopathic thrombocytopenic purpura (ITP)* Drug-associated, especially quinine,gold penicillammin and anticonvulsants drugs Coagulation activation Disseminated intravascular coagulation (DIC) Mechanical pooling Hypersplenism

Thrombotic microangiopathies : Haemolytic uraemic syndrome Liver disease Thrombotic thrombocytopenic purpura Others : Gestational thrombocytopenia Type 2B von Willebrand disease

Such transfusions provide only temporary relief because the survival of the platelets in the circulation is a few days at most, and only a matter of minutes or hours if the thrombocytopenia is due to increased platelet consumption, as in idiopathic thrombocytopenic purpura


Idiopathic thrombocytopenic purpura ITP is mediated by autoantibodies, most often directed against the platelet membrane glycoprotein IIb/IIIa, which sensitise the platelet, resulting in premature removal from the circulation by cells of the reticulo-endothelial system. It is not a single disorder; some cases occur in isolation while others are associated with underlying immune dysregulation in conditions such as connective tissue diseases, HIV infection, B cell malignancies, pregnancy and certain drug therapies.



Unlike ITP in children, it is unusual for there to be a history of a preceding viral infection. Symptoms or signs of a connective tissue disease may be apparent at presentation or emerge several years later.


Patients aged over 65 years should have a bone marrow examination to look for an accompanying B cell malignancy and appropriate autoantibody testing performed if a diagnosis of connective tissue disease is likely. HIV testing should be considered. The peripheral blood film is normal, apart from a greatly reduced platelet number, whilst the bone marrow reveals an obvious increase in megakaryocytes.

Bleeding tendency: dry Purpura

Ecchymosis > 3mm

Bleeding tendency : dry Purpura

Petechiae < 3mm

Persistent or potentially life-threatening bleeding should be treated with platelet transfusion in addition to the other therapies. The condition may become chronic, with remissions and relapses. 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. If significant bleeding persists despite splenectomy, low-dose corticosteroid therapy, immunosuppressive therapy such as rituximab, ciclosporin and tacrolimus should be considered.

Coagulation disorders: Coagulation factor deficiency may be congenital or acquired and may affect one or several of the coagulation factors . Von Willebrand disease is the most common inherited bleeding disorder. Haemophilia A and B are the most common single coagulation factor deficiencies. Acquired disorders may be due to under-production (e.g. in liver failure), increased consumption (e.g. in disseminated intravascular coagulation) or inhibition of function (such as heparin therapy or immune inhibitors of coagulation, e.g. acquired haemophilia A).

Immune-mediated Acquired haemophilia and von Willebrand syndrome Others Acquired factor X deficiency (in amyloid) Acquired von Willebrand syndrome in Wilms tumour 3-Drug-induced Inhibition of function Heparins Lepirudin Fondaparinux Rivaroxaban Dabigatran Inhibition of synthesis Warfarin
Causes of coagulopathy A-Congenital : X-linked Haemophilia A and B Autosomal Von Willebrand disease Factor II, V, VII, X, XI and XIII deficiencies Combined II, VII, IX and X deficiency Combined V and VIII deficiency Hypofibrinogenaemia Dysfibrinogenaemia B-Acquired: 1-Underproduction Liver failure 2-Increased consumption Coagulation activation Disseminated intravascular coagulation (DIC)

Haemophilia A Factor VIII deficiency resulting in haemophilia A affects 1/10 000 individuals. It is the most common congenital coagulation factor deficiency. Factor VIII is primarily synthesised by the liver and endothelial cells, and has a half-life of about 12 hours. It is protected from proteolysis in the circulation by binding to von Willebrand factor (vWF).


Relation between vonWillebrand’s Factor (vWF) and Factor VIII vWF
VIII


Genetics: The factor VIII gene is located on the X chromosome. Severe haemophilia is associated with large deletions in the gene, while single-base changes more often result in moderate or mild disease. As the factor VIII gene is on the X chromosome, haemophilia A is a sex-linked disorder . Thus all daughters of haemophiliacs are obligate carriers and they, in turn, have a 1 in 4 chance of each pregnancy resulting in the birth of an affected male baby, a normal male baby, a carrier female or a normal female. Antenatal diagnosis by chorionic villous sampling is possible in families with a known mutation.

* Hemophilia inheritance

* Hemophilia inheritance


Haemophilia 'breeds true' within a family; all members have the same factor VIII gene mutation and a similarly severe or mild phenotype. Female carriers of haemophilia may have reduced factor VIII levels because of random inactivation of their normal X chromosome in the developing fetus (lyonisation). This can result in a mild bleeding disorder; thus all known or suspected carriers of haemophilia should have their factor VIII level measured.

Severity of haemophilia (ISTH criteria)

Clinical presentation
Factor VIII or IX level
Degree of severity
Spontaneous haemarthroses and muscle haematomas
›0.01U/mL Severe
Mild trauma or surgery causes bleeding
0.01-0.05 U/mL
Moderate
Major injury or surgery results in excess bleeding
›0.05› 0.4U/mL Mild



The extent and patterns of bleeding are closely related to residual factor VIII levels. Patients with severe haemophilia (< 1% of normal factor VIII levels) present with spontaneous bleeding into skin, muscle and joints. Retroperitoneal and intracranial bleeding is also a feature. Babies with severe haemophilia have an increased risk of intracranial haemorrhage and, although there is insufficient evidence to recommend routine caesarean section for these births,

It is appropriate to avoid head trauma and to perform imaging of the newborn within the first 24 hours of life. Individuals with moderate and mild haemophilia (factor VIII levels 1-40%) present with the same pattern of bleeding, but usually after trauma or surgery when bleeding is greater than would be expected from the severity of the insult.

Hemophilia (Hemarthrosis)

Knee Joint

Hematomas

Hemophilia

Hematoma

Hemophilia

S/C HEMATOMA

Hemophilia



Long term sequels of hemophilia : Deformities due to recurrent hemarthrosis and permanent joint damage and muscle atrophy
Hemophilia

Long-term sequels of Hemophilia: Permanent damage to knee and elbow joints.

Hemophilia A
A sex linked inherited disorder charact-erized by deficiency of factor VIII. Clinically : Males are affected. Features start usually when the infant starts to crawl. One of the main features is Hemarthrosis (bleeding into joints). Bleeding into muscles, S/C tissue, after any injury or surgery, painless hematuria, GI bleeding.

Diagnosis of hemophilia A

Platelets count : usually normal in count.Prothrombin Time : normal.Activated Partial thromboplastin time : prolonged.Thrombin time : normal.Bleeding time : normal.Factor VIII assay : reduced Factor VIII concentration (NR 50-200 U/dl)Anaemia maybe present, relevant to bleeding –IDA.

The major morbidity of recurrent bleeding in severe haemophilia is musculoskeletal. Bleeding is typically into large joints, especially knees, elbows, ankles and hips. Muscle haematomas are also characteristic, most commonly in the calf and psoas muscles. If early treatment is not given to arrest bleeding, a hot, swollen and very painful joint or muscle haematoma develops. Recurrent bleeding into joints leads to synovial hypertrophy, destruction of the cartilage and secondary osteoarthrosis. Complications of muscle haematomas depend on their location.

A large psoas bleed may extend to compress the femoral nerve; calf haematomas may increase pressure within the inflexible fascial sheath causing a compartment syndrome with ischaemia, necrosis, fibrosis, and subsequent contraction and shortening of the Achilles tendon.


In addition to raising factor VIII concentrations, resting of the bleeding site by either bed rest or a splint reduces continuing haemorrhage. Once bleeding has settled, the patient should be mobilised and physiotherapy used to restore strength to the surrounding muscles. The vasopressin receptor agonist DDAVP raises the vWF and factor VIII levels by 3-4-fold, which is useful in arresting bleeding in patients with mild or moderate haemophilia A. The dose required for this purpose is high, typically 0.3 μg/kg given intravenously or subcutaneously.

Alternatively, the same effect can be achieved by intranasal administration of 300 μg. Following repeated administration of DDAVP, patients need to be monitored for evidence of water retention which can result in significant hyponatraemia .In addition to treatment 'on demand' for bleeding, factor VIII can be administered 2 or 3 times per week as 'prophylaxis' to prevent bleeding in severe haemophilia. This is most appropriate in children, but its widespread use is limited by the high cost of factor VIII preparations


FVIII dose (IU) = Target FVIII levels – FVIII baseline levels x body weight (kg) x 0.5 unit/kg One unit of FVIII per kilogram of body weight increases the plasma FVIII level by 2%.The FVIII half-life of 8–12 h requires injections twice a day to maintain therapeutic levels, whereas the FIX half-life is longer, ~24 h, so that once-a-day injection is sufficient. Cryoprecipitate is enriched with FVIII protein (each bag contains ~80 IU of FVIII)

* So what is the practical rule to use?

1 unit of FVIII per Kg will raise FVIII plasma level by 2%. Example : how much do I need to raise Factor VIII to 30% in a 70 kg man : 70 x 30 / 2 = 1050 unit.


Complications of coagulation factor therapy: Before 1986, coagulation factor concentrates from human plasma were not virally inactivated with heat or chemicals, and many patients became infected with HIV and the hepatitis viruses HBV and HCV. In exposed patients with severe haemophilia, infection with HCV is almost universal, 80-90% have evidence of HBV exposure, and 60% became HIV-positive. viral inactivation of these blood products has eradicated the risk of viral infection.

Concern that the infectious agent which causes vCJD might be transmissible by blood and blood products has been confirmed in recipients of red cell transfusion, and in at least one recipient of factor VIII. Another serious complication of factor VIII infusion is the development of anti-factor VIII antibodies, which arise in about 20% of severe haemophiliacs. Such antibodies rapidly neutralise therapeutic infusions, making treatment relatively ineffective. Infusions of activated clotting factors, e.g. VIIa or FEIBA (factor eight inhibitor bypassing activity-an activated concentrate of factors II, IX and X), may stop bleeding.

Haemophilia B (Christmas disease) Aberrations of the factor IX gene, which is also present on the X chromosome, result in a reduction of the plasma factor IX level, giving rise to haemophilia B. This disorder is clinically indistinguishable from haemophilia A but is less common. The frequency of bleeding episodes is related to the severity of the deficiency of the plasma factor IX level. Treatment is with a factor IX concentrate, used in much the same way as factor VIII for haemophilia A.


dosing : 1 unit / kg of F IX will raise Factor IX by 1%.FIX dose (IU) = Target FIX levels – FIX baseline levels x body weight (kg) x 1.0 unit/kg Although factor IX concentrates shared the problems of virus transmission seen with factor VIII, they do not commonly induce inhibitor antibodies (< 1% patients); when this does occur, however, it may be heralded by the development of a severe allergic-type reaction.

vonWillebrand’s Disease

The most common inherited coagulation disorder, due to deficiency of vonWillebrand’s factor. vWF is a protein synthesised by endothelial cells and megakaryocytes, This disorder is inherited mostly as autosomal dominant.VonWillebrand’s factor is present in both plasma and platelets and acts as : 1. A carrier protein of Factor VIII. 2.It is also plays an important role in platelets adhesion to subendothelium.

Relation between vonWillebrand’s Factor (vWF) and Factor VIII vWF

VIII

Clinical features of vW disease :

Mucous membrane bleeding, particularly epistaxis and menorrhagia. Bruising and bleeding after trauma or during surgery are also common. Haemarthrosis unlikely. Within a single family the disease has variable penetrance, so that some members may have quite severe and frequent bleeds, whereas others are relatively asymptomatic.

Diagnosis of vW disease

Platelets count : normal. Bleeding time : Classically prolonged. Prothrombin Time : normal. Activated Partial thromboplastin time : classically prolonged. Thrombin Time is normal. Factor VIII and vW factor concentrations are classically reduced.

Management of VW disease:

General measures. Tranexamic acid may be useful in mucosal bleeding. Cryoprecipitate. Factor VIII concentrate. Desmopressin (intranasal). mild haemorrhage can be successfully treated with desmopressin, which raises the vWF level.


ACQUIRED BLEEDINGDISORDERS DISSEMINATED INTRAVASCULAR COAGULATION (DIC) Clinical features: DIC can be initiated by a variety of different mechanisms in a number of diverse but distinct clinical situations. Endothelial damage, due to many causes-e.g. endotoxaemia due to Gram-negative septicaemia-results in tissue factor expression, which leads to activation of the coagulation cascade through the extrinsic pathway .

Intravascular coagulation takes place with consumption of platelets, factors V and VIII, and fibrinogen. This results in a potential haemorrhagic state, due to the depletion of haemostatic components, which may be exacerbated by activation of the fibrinolytic system secondary to the deposition of fibrin.

CAUSES OF DISSEMINATED INTRAVASCULAR COAGULATION

Infections: E. coli Neisseria meningitidis Streptococcus pneumoniae Malaria Cancers: Lung Pancreas Prostate
Obstetric: Placental abruption Retained dead fetus Pre-eclampsia Amniotic fluid embolism Tissue Damage : Trauma Closed head injury Burns Hypoperfusion or hypotension Exogenous Causes: (Snake venom)


Investigations: Definitive diagnosis depends on the finding of: thrombocytopenia, prolongation of the prothrombin time (due to factor V and fibrinogen deficiency) and activated partial thromboplastin time (due to factors V, VIII and fibrinogen deficiency), a low fibrinogen concentration and increased levels of D-dimer (cleaved from fibrin by plasmin, establishing evidence of fibrin lysis).


ISTH scoring system for diagnosis of DIC Presence of an associated disorderPlatelets:> 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)

Management Therapy should be aimed at treating the underlying condition causing the DIC, e.g. intravenous antibiotics for suspected septicaemia. Exacerbating factors such as acidosis, dehydration, renal failure and hypoxia should be corrected. If the patient is bleeding, blood products such as platelets and/or fresh frozen plasma should be given to correct identified abnormalities. It may also be reasonable to treat severe coagulation abnormalities in the absence of frank bleeding to prevent sudden catastrophic haemorrhage such as an intracranial bleed or massive gastrointestinal haemorrhage.


LIVER DISEASE In severe parenchymal liver disease , bleeding may arise from many different causes. Local anatomical abnormalities are often the site of major bleeding (such as oesophageal varices or peptic ulcer), and this may be difficult to arrest because of deficiencies in components of the haemostatic system. These may arise because of reduced hepatic synthesis, e.g. factors II, VII, IX, X and fibrinogen, DIC, reduced clearance of plasminogen activator, or thrombocytopenia secondary to hypersplenism.

Treatment should be reserved for acute bleeds or to cover interventional procedures such as liver biopsy. Cholestatic jaundice reduces vitamin K absorption and leads to a deficiency of function of factors II, VII, IX and X due to reduced gamma glutamate carboxylation. This deficiency can be readily and effectively treated with vitamin K1 10 mg daily parenterally for several days.

RENAL FAILURE: The severity of the haemorrhagic state in renal failure is proportional to the plasma urea concentration . Bleeding manifestations are of platelet type, with gastrointestinal haemorrhage being particularly common. The causes are multifactorial, including anaemia, mild thrombocytopenia and the accumulation of low molecular waste products, normally excreted by the kidney, that inhibit platelet function.

Treatment is by dialysis to reduce the urea concentration, platelet concentrate infusions and red cell transfusions to raise the haemoglobin and decrease the propensity to bleed. Increasing the concentration of vWF, either by cryoprecipitate or by desmopressin (DDAVP), may promote haemostasis.