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Keywords:

  • platelet function disorders;
  • Glanzmann Thrombasthenia;
  • Bernard–Soulier Syndrome

Summary

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Severe platelet function defects are rare disorders that require expertise in diagnosis and management. Therefore patients with such disorders should be referred to and managed in centres with the full laboratory repertoire of tests and clinical support necessary to optimise their quality of care. The aim of this review is to discuss the management of these patients in various clinical situations including surgical intervention.

Severe platelet function disorders are very rare disorders, the most common of which are the disorders due to deficiencies of platelet surface glycoprotein; Bernard–Soulier Syndrome and Glanzmann Thrombasthenia (GT). However milder conditions, such as platelet storage pool disease, can also occasionally exhibit a severe phenotype.

Bernard–Soulier Syndrome (BSS)

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

BSS is a platelet membrane receptor defect and was first described in 1948 in a young male with severe clinical bleeding, prolonged bleeding time and macrothrombocytopenia. It has an estimated incidence of <1 in 1 million although this is likely to be an underestimate due to misdiagnosis and underreporting (Lopez et al, 1998). The inheritance is generally autosomal recessive and often associated with consanguinity but occasional autosomal dominant forms have also been reported (Miller et al, 1992; Lopez et al, 1998; Vettore et al, 2008). The bleeding tendency is attributed to the dysfunction or absence of the glycoprotein (gp)Ib-IX-V complex (Clemetson et al, 1982; Berndt et al, 1983), resulting in abnormal initiation and adhesion of platelets to subendothelial-bound von Willebrand Factor (VWF) during the formation of platelet plug. The genes GP1BA, GP1BB, GP9 and GP5 are responsible for the formation of each of the subunits of the gpIb-IX-V complex on the platelet membrane and several mutations in the form of missense mutations, nonsense mutations and frameshift insertions/deletions have been reported in GP1BA, GP1BB and GP9 (Ware et al, 1990; Kunishima et al, 1994; Noda et al, 1995; Mitsui et al, 1998). Lack of gpIb-IX results in the formation of large platelets leading to the inference that gpIb-IX complex has a role in normal megakaryocyte maturation and regulation of platelet size (Mhawech & Saleem, 2000).

BSS generally presents in infancy with symptoms of abnormal primary haemostasis in the form of epistaxis, gingival bleeding, purpura and bruising. Although this is the typical presentation, there is considerable variation in severity and age of onset of bleeding between individuals. Invasive procedures or trauma are more commonly associated with excessive and sometimes severe bleeding. Haemarthrosis, intracranial haemorrhage and deep visceral bleeding are relatively uncommon (George et al, 1990; Tsementzis & Marsh, 1991). Later in life, menorrhagia may become a significant issue. Haematuria and gastro-intestinal bleeding may also occur. Platelet counts in BSS may be very low (<30 × 109/l), marginally low or normal (∼200 × 109/l) and can fluctuate with time in the same individual (Lopez et al, 1998).

The diagnosis of BSS involves assessment of the blood count, which usually shows an elevated Mean Platelet Volume (MPV) and careful examination of the blood film for characteristic large platelets. The large platelets are often mistaken for erythrocytes in automated impedence-based counters and a more accurate count can be obtained using optical counters or manual counting. The PFA-100 (Platelet Function Analyser) is an in vitro measure of the bleeding time and shows absent closure times on collagen/adenosine diphosphate (ADP) and collagen/adrenaline cartridges. Platelet aggregation in response to ADP, collagen and arachidonic acid (AA) is normal but agglutination to ristocetin is absent. Unlike the pattern in von Willebrand disease (VWD), this defect is not corrected by the addition of normal plasma. Flow cytometric analysis using a panel of antibodies specific for each component of the complex (CD 42a–d) to characterize the decrease in the gpIb-IX-V membrane receptor can confirm the diagnosis (Simon et al, 2008) and is a very valuable diagnostic tool, particularly in infants in whom obtaining sufficient blood for platelet aggregation studies is difficult.

Glanzmann Thrombasthenia (GT)

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Glanzmann Thrombasthenia (GT) is an autosomal recessive bleeding disorder initially described by Glanzmann in 1918. Like BSS, the incidence is higher in communities where consanguinity is prevalent. The defect is caused by quantitative or qualitative abnormalities of the gpIIb/IIIa integrin platelet membrane receptor resulting in abnormal platelet aggregation. In normal individuals activated gpIIb/IIIa binds to fibrinogen and VWF which cross-link platelets into aggregates (Nurden & George, 2005). In GT the platelets are able to interact with the collagen in the subendothelium but inter-platelet interactions are defective and thrombus production is abnormal (Patel et al, 2003). Clot retraction is also often absent (Nurden & Nurden, 2008). Multiple mutations can affect the gpIIb/IIIa complex assembly on the platelet membrane. Nonsense mutations, splice site mutations with frameshifts and missense mutations have been reported in either the αIIb (ITGA2B) or β3 (ITGB3) gene (George et al, 1990; Nurden & George, 2005; Nurden & Nurden, 2008). Carrier states bearing 50% gpIIb/IIIa molecules may be asymptomatic but those with Type 2 GT (10–20% gpIIb/IIIa) may be severely affected. Type 1 GT typically have <5% gpIIb/IIIa and have absent or severely deficient fibrinogen binding and clot retraction. Platelets in the GT Type 3 (variant) have a differential ability to retract fibrin clot and contain variable levels of fibrinogen (Simon et al, 2008). Although patients with severe GT present early, clinical observations have shown no consistent correlation between the levels of gpIIb/IIIa and severity of haemorrhagic disease. This discrepancy was recorded in patients with severe GT where the onset of bleeding manifestations ranged from neonatal purpura to first haemorrhagic symptoms in adolescence or adulthood (George et al 1990).

There is variability in the manifestations of haemorrhagic symptoms in GT. Although the majority present in early childhood and suffer frequent bleeding episodes through the first decade of life, some patients bleed infrequently and rarely need intervention. In those who have a severe phenotype from the outset, the severity of symptoms may decrease with age, reflecting changing lifestyle, but in female patients this is less likely as challenges in the form of menstrual periods and childbirth remain. The typical symptoms are similar to those of BSS and characterized by mucocutaneous haemorrhage. Gingival haemorrhage is a constant finding and menorrhagia especially at menarche may be particularly severe. In general the symptoms of bleeding in severe platelet function disorders are worse in women and this relates mainly to excessive menstrual blood loss. Bleeding after trauma and surgical procedures may also be severe (George et al, 1990).

Platelet count and morphology is normal in GT. There is absent closure on the PFA-100 with absent or impaired platelet aggregation response to all agonists except ristocetin. The diagnosis can be confirmed by flow cytometry by determining the quantity of gpIIb–IIIa expressed on the platelet membrane using specific antibodies binding to either gpIIIa (CD61) or gpIIb (CD 41). As with BSS this is a very useful diagnostic tool in infants.

Apart from BSS and GT, deficiencies of other platelet glycoproteins are even rarer and tend to have a mild bleeding phenotype. Platelet function defects can also result from abnormalities of platelet granules. The defect may be in the number of granules, granule content or failure of secretion of either dense granules or α-granules but combined deficiencies of both α-granules and dense granules have also been reported. Although generally of mild to moderate severity, significant bleeding may result following surgery or trauma. Quebec platelet syndrome is an extremely rare autosomal dominant disorder characterised by overexpression of urokinase plasminogen activator with low levels of platelet factor V. Affected individuals exposed to haemostatic challenges without antifibrinolytic therapy may present with severe bleeding (Diamandis et al, 2008). These patients have unusual symptoms characterized by moderate to severe delayed bleeding beginning 12–24 h after trauma or surgery. The haemorrhagic manifestations are controlled by antifibrinolytics but do not respond to platelet transfusion. It is associated with reduced to low-normal platelet counts, proteolytic degradation of soluble and membrane proteins stored in platelet alpha granules, an apparent quantitative deficiency of the alpha granule protein multimerin, and defective aggregation with adrenaline (Kahr et al, 2001).

General management of severe platelet function disorders

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Patients with severe platelet function disorders are susceptible to spontaneous bleeding and haemorrhage secondary to trauma or surgical intervention. These patients require specialist management and should be registered with a haemophilia centre with diagnostic and 24-h treatment access facilities. The patients must be issued with an identification card bearing the clinical condition along with written information about the condition and relevant contact numbers of the treatment centre. Patients must be advised with regard to avoiding aspirin, aspirin-like drugs and non-steroidal anti-inflammatory drugs and advised regarding dental hygiene (Bolton-Maggs et al, 2006).

Careful assessment of the symptoms and appropriate laboratory evaluation is important in making the diagnosis. Family history, including consanguinity, can be important in identifying other members at risk of having the condition (Hayward et al, 2006).

Many of these patients will be exposed to blood products in their life span. It is important that they are immunized against hepatitis A and B and annual liver function tests should be part of their general surveillance (Makris et al, 2003). All patients should be human leucocyte antigen (HLA) typed to facilitate HLA-selected platelet units for transfusion and the rationale for this recommendation is discussed in the platelet transfusion section below. This information will also be useful to anticipate platelet refractoriness especially when formulating plans for surgical interventions and haemorrhagic situations.

Agents used in the management of platelet function disorders

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Desmopressin

The synthetic analogue of vasopressin, 1-deamino-8-d-arginine vasopressin (DDAVP, desmopressin) has been successfully used for the management of congenital and acquired platelet function defects (Mannucci, 1988; Coppola & Di Minno, 2008). Although of limited benefit in platelet receptor deficiencies, patients with storage pool disorders may respond to treatment with desmopressin (Nieuwenhuis & Sixma, 1988; Wijermans & van Dorp, 1989; Rao et al, 1995; Español et al, 1998; Kosch et al, 1999; Zatik et al, 2002). It affects haemostasis by causing endogenous release of Factor VIII, VWF, tissue plasminogen activator and also increasing platelet adhesiveness (Lethagen & Nilsson, 1992; Lozano et al, 1999) as well as aggregation at high shear rates (Cattaneo et al, 1994). There is some documented efficacy in BSS which suggests that desmopressin can shorten the prolonged bleeding time through mechanisms independent of released VWF (Cattaneo, 2002) illustrating that many aspects of cellular mechanisms involved in the action of desmopressin are still unclear (Coppola & Di Minno, 2008).

Thus, the role of desmopressin in severe platelet disorders is limited. A desmopressin trial using PFA-100 may be considered in patients with storage pool disorders with severe phenotype. Improvements in bleeding times and clinical efficacy have been noted in some but not all patients with storage pool disorders following desmopressin (Wijermans & van Dorp, 1989; Rao et al, 1995; Español et al, 1998; Kosch et al, 1999; Zatik et al, 2002). Correction of bleeding time after desmopressin administration has been reported in BSS (Cuthbert et al, 1988; Di Michele & Hathaway, 1990). A desmopressin trial using PFA-100 prior to invasive procedures or during bleeding episodes may be considered in BSS bearing in mind that response rates are variable and may not represent in vivo haemostasis in these situations. Performing a desmopressin trial is probably not worthwhile in GT and efficacy is difficult to measure, though its use could be considered in GT in conjunction with other therapy in situations where bleeding is severe.

Desmopressin can be administered intravenously, subcutaneously or by nasal spray. Peak levels are reached 30–60 min after an intravenous injection and 90–120 min after subcutaneous and intranasal administration (Mannucci, 1997). The choice of route of administration of desmopressin depends on the procedure and clinical condition. Intravenous dose of desmopressin is 0·3 μg/kg diluted in 20–50 ml of saline administered over 30 min starting an hour before the planned procedure. The dose for the concentrated intranasal spray (Octim) is 150 μg per dose for a child under 50 kg in weight and 300 μg per dose in an adult. This dose can lead to side effects in the form of fluid retention that lasts approximately 12 h, hyponatremia, hypotension, facial flushing and mild headaches (Nolan et al, 2000; Hayward et al, 2006). The risk of fluid retention and hyponatremic seizures makes desmopressin unsuitable for very small children and should be avoided in those younger than 2 years of age. It is important to advise patients to restrict fluid intake for 24 h following desmopressin administration.

Anti-fibrinolytics

Anti-fibrinolytics are a useful adjunct in preventing and controlling bleeding. Minor bleeding, such as epistaxis or gingival haemorrhage, may respond to these alone and in more invasive procedures, they are used in conjunction with another therapy, such as platelet transfusion or desmopressin (Hayward, 2005). It is important to avoid using anti-fibrinolytics in the presence of haematuria due to the risk of clots in the renal pelvis and ureters and cautious use is recommended in high thrombotic risk procedures. All patients with severe platelet function defects should have a ready supply of anti-fibrinolytics at home for use if required. The dose of tranexamic acid (the most commonly used anti-fibrinolytic in the UK) is 15–25 mg/kg three times daily orally or 10–15 mg/kg three times daily by intravenous route and upto four times daily in selected cases. Epsilon aminocaproic acid is given at a dose of 100 mg/kg infused over 15 min, followed by a maintenance dose of 10 mg/kg/h or 5 g bolus very 4 h.

Platelet transfusion

Platelet transfusion provides healthy allogeneic platelets, partially correcting the functional defect in patients with severe platelet function disorders who do not respond to other therapy. The risks of platelet transfusion are multiple, including alloimmunization, risk of transfusion transmitted infections and allergic reactions. Each platelet pool is obtained from four to six pooled whole blood donations but single donor apheresis collections reduce donor exposure.

Multiple platelet transfusions also present the risk of development of alloantibodies to HLA antigens or missing glycoproteins in BSS and GT (George et al, 1990). Some isoantibodies recognize specific epitopes, like the platelet integrin αIIbβ3 on the active sites of the glycoproteins, rendering transfused platelets refractory and leading to accelerated destruction (Nurden & Nurden, 2008). This risk appears to be higher for GT than BSS and can limit future responses to platelet transfusions (Hayward et al, 2006). Since the introduction of leucocyte depleted blood components the incidence of HLA alloimmunization is reported to be small (Novotny, 1999) and the BCSH guidelines have therefore suggested that it is no longer necessary to use HLA-matched platelet transfusions in GT and BSS (BCSH, 2003). However a recent review by the United Kingdom Haemophilia Centre Doctors’ Organization (UKHCDO) still recommended the use of HLA-selected platelets in these patients because the evidence is based on studies in immunodeficient patients and not immunocompetent patients with inherited platelet disorders (Bolton-Maggs et al, 2006). Our recommendation is in agreement with the UKHCDO; to transfuse HLA-matched platelets in these patients but, because of the risks discussed above, caution and careful planning must be instituted prior to platelet transfusion.

Recombinant VIIa (rVIIa)

The use of rVIIa to treat bleeding episodes in platelet function disorders was initially reported in a child with GT who had not responded to conservative treatment for epistaxis (Tengborn & Petruson, 1996). There have since been other reports of its successful use (Poon et al, 1999; d’Oiron et al, 2000; Patel et al, 2001; Almeida et al, 2003; Bell & Savidge, 2003) and rVIIa is now licensed for use in GT with gpIIb/IIIa and/or HLA antibodies with past or present refractoriness to platelet transfusions. It has been used to cover minor procedures and in GT it can be used early in more serious bleeding episodes if availability of matched platelets is anticipated to cause delay in treatment. However the licensing is restricted to those patients with antibodies to gpIIb/IIIa or platelet refractoriness and the cost implication is an important consideration. A single dose rounded up to 90 μg/kg in a child weighing 20 kg works out to £1070·73 and that in a 70 kg patient reaches £3747·56. The International Survey on the off-label use of rVIIa in GT reported the reasons for its use, which included platelet inefficacy for the current and/or previous bleeds in 49%, history of antiplatelet immunization in 42% and prevention of antiplatelet immunization in 43% (Poon et al, 2004). Data from the International Registry on rVIIa and Congenital Platelet Disorders suggest that rVIIa is a relatively effective and safe alternative to platelets for both treatment of acute bleeding episode and surgical prophylaxis in patients with GT (Poon et al, 2001). Recombinant VIIa is thought to enhance thrombin generation by both tissue factor-dependent and -independent mechanisms (ten Cate et al, 1993; Lisman et al, 2002, 2004). It helps to form a tighter fibrin network with reduced permeability resulting in improved haemostatic efficacy in patients with GT. The thrombin generation capacity has been shown to increase significantly after 90 μg/kg dose of rVIIa in this group of patients. It has also been suggested that rVIIa has an activating effect on platelets through increased phosphatidyl-serine exposure on the platelet surface and an increase in platelet-derived circulating microparticles (Dargaud, 2006). There is variation in practice and the use of higher doses, of upto 270 μg/kg, have been reported although this is not the licenced dose (Chuansumrit et al, 1999). The recommended dose of rVIIa is 90 μg/kg intravenously given at an interval of 2 h if required for 3 doses or until bleeding stops (Poon et al, 2004; Poon, 2007). Recommendation for the use of rVIIa for severe platelet disorders in this review refers to patients with GT unless stated otherwise.

Other therapies

Bone marrow transplantation.  The first bone marrow transplant in GT was reported in 1985 in a 4 year-old boy with anti- gpIIb/IIIa antibodies from his brother who was heterozygous for the condition. The initial transplant was rejected but a second transplant with CCNU, cyclophosphamide, procarbazine and horse antihuman thymocyte globulin in the preparative regimen was successful (Bellucci et al, 1985). Engraftment was confirmed by platelet aggregation tests or flow cytometry demonstrating the presence of membrane gpIIb/IIIa at 50% of the normal values, in keeping with heterozygous state of the donor. Since then, there have been other successful transplants and, to date, 14 patients with GT have been successfully transplanted (Johnson et al, 1994; McColl & Gibson, 1997; Bellucci et al, 2000; Flood et al, 2005; Connor et al, 2008; Ishaqi et al, 2009; Miller et al, 2009; Table I). A successful transplant was reported in a patient with GT and acute myeloid leukaemia (AML) in second remission from an HLA-matched unrelated donor (Fujimoto et al, 2005). Sustained engraftment has been achieved despite the presence of anti-platelet antibodies in some reported GT transplant cases (Bellucci et al, 1985, 2000; Flood et al, 2005; Ishaqi et al, 2009). Three patients received reduced intensity conditioning with fludarabine 30 mg/m2, alemtuzumab 0·2 mg/kg and melphalan 140 mg/m2 with successful outcomes (Connor et al, 2008). Three patients received unrelated donor transplants (including indication for AML) and family (non sibling) donor transplants were performed in two patients (Flood et al, 2005; Fujimoto et al, 2005; Connor et al, 2008). Of the 14 patients transplanted for GT, nine were female, indicating that concern over potential complications of pregnancy and childbirth as well as menstruation may well impact on the clinicians’ and family/patient’s decision on treatment choices.

Table I.   Characteristics of patients transplanted for Glanzmann thrombasthenia.
Pt No.ReferenceAge at diagnosisAge at SCT (years)Bleeding historyDonorSex of patient/donorAnti gpIIb/IIIa antibodiesConditioning regimen
  1. SCT, stem cell transplantation; M, male; F, female; MUD, matched unrelated donor; MFD, matched family donor; UD, unrelated donor; UCB, umbilical cord blood; RIC, reduced-intensity conditioning; Flu, fludarabine; Mel, melphalan; Alem, alemtuzumab; Bu, busulfan; Cy, cyclophosphamide; ATG, antithymocyte globulin; ND not described.

 1Bellucci et al (1985)2 years4Life-threatening bleedsHLA-identical brother (heterozygous)M/MPositiveCy/radiation CCNU, Cy, procarbazine, ATG
 2Bellucci et al (2000)2 years16 HLA-identical brother (heterozygous)F/MPositiveBu/Cy
 3Johnson et al (1994)16 weeks2·5Recurrent bleedingHLA-identical sister (heterozygous)F/FNDBu/Cy
 4McColl and Gibson (1997)1 d5Life-threatening bleedsHLA-identical brotherM/MNDBu/Cy
 5Flood et al (2005)Soon after birth6Severe bleedingHLA-UDF/NAPositiveFlu/Bu/Cy
 6Flood et al (2005)Soon after birth5Severe bleedingHLA-identical sisterF/FPositiveFlu/Bu/Cy
 7Flood et al (2005)42 d1·5Severe bleeding M/MNDFlu/Bu/Cy
 8Ishaqi et al (2009)60 d11Severe bleedingHLA-identical brother (heterozygous)F/MPositiveBu/Cy, Alem
 9Connor et al (2008)98 d3Severe bleedingMUDF/MNDRIC – Flu/Mel, Alem
10Connor et al (2008)140 d12Life-threatening bleedsMFDF/MNon specific anti platelet antibodiesRIC – Flu/Mel, Alem
11Connor et al (2008)108 d10Life-threatening bleedsHLA-identical brotherF/MHLA antibodiesBu/Cy
12Connor et al (2008)111 d4Severe bleedingHLA-identical sisterM/FNDBu/Cy
13Connor et al (2008)1 d2Severe bleedingMFDF/FNDRIC – Flu/Mel, Alem
14Miller et al (2009)ND3·5Life-threatening bleedsUnrelated UCBM/FNegativeBu/Cy, ATG

Bone marrow transplantation from HLA-identical donors has also shown to be successful in BSS with severe haemorrhagic symptoms and/or alloantibody directed against gpIb/IX/V complex, leading to platelet refractoriness. A pair of twin girls with BSS and gpIb/IX/V antibodies were transplanted from their HLA-identical brother following mild-intensity conditioning regimen of busulfan (8 mg/kg of body weight), thiotepa (6 mg/kg), and fludarabine (160 mg/m2) and flow cytometry analysis post-transplant confirmed the presence of glycoprotein Ib/IX/V complex on the platelet surface membrane (Locatelli et al, 2003). A 28-year old female was transplanted with peripheral blood stem cells from her HLA-identical brother with good clinical outcome and normal platelet aggregation tests post-transplant (Rieger et al, 2006).

Some authors recommend early bone marrow transplantation to prevent the complications of alloimmunization whereas others advocate this only in those with severe disease. In patients with severe, persistent and life-threatening haemorrhages, and/or gpIIb/IIIa alloantibodies and platelet refractoriness, stem cell transplant from an HLA-matched donor is an appropriate therapeutic option, but careful evaluation of the risk-benefit of such a procedure needs to be assessed on an individual basis (Bellucci et al, 2000; Connor et al, 2008).

Gene therapy.  Research is ongoing in the field of gene therapy for platelet function disorders specifically addressing GT. Megakaryocyte-specific expression of integrin αIIbβ3 is caused by the presence of regulatory elements of the αIIb promoter resulting in selective gene transcription early in megakaryocytopoiesis. The use of αIIb promoter driven MuLV (murine leukaemia retrovirus) vectors for gene transfer of hematopoietic CD34+ cells to target transgene expression in developing megakaryocytes has suggested potential applications of human gene therapy for platelet disorders (Wilcox et al, 1999). Successful transduction of peripheral blood CD34+ cells has been demonstrated in vitro from two patients with GT using MuLV with expression of αIIbβ3 on transduced megakaryocytes. This expression was suboptimal but still resulted in correction of GT (Wilcox et al, 2000).

The feasibility of gene therapy for correcting molecular defects in platelets has been investigated by targeted expression of the human integrin β3-subunit in megakaryocytes of β3−/− mice affected with GT (Fang et al, 2005). Mononuclear cells were isolated from bone marrow of β3−/− mice, transduced with β3 lentivirus and transplanted into lethally irradiated β3−/− littermates as a model for autologous hematopoietic stem cell gene therapy. These mice not only expressed integrin β3 on their platelets but also demonstrated correction of platelet function as demonstrated by aggregation studies. Tolerance of the host for the newly expressed proteins is an important issue; however attempts at reducing therapy-related toxicity using non-myeloablative protocols are also being explored (Wilcox & White, 2003). Development of αIIbβ3 antibodies is a potential complication of human gene therapy for GT but intravenous immunoglobulin was shown to effectively diminish platelet clearance and restore platelet function in the mouse model (Fang et al, 2005). Although this work suggests a possible cure for the future, it is unlikely to be a realistic option for GT patients for some years yet.

Management of spontaneous and traumatic bleeds (Table II)

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References
Table II.   Investigation and management of severe platelet function disorders.
InvestigationBleedsSurgeryPregnancy
  1. FBC, full blood count; MPV, man platelet volume; rVIIA, recombinant activated factor VII; IUD, intrauterine device.

  2. *Glanzmann Thrombasthaenia (GT) with gpIIb/IIIa antibodies and/or HLA with past or present refractoriness to platelet transfusions or severe haemorrhage/complex surgical procedure.

  3. †Newborn at risk of GT/Bernard Soulier Syndrome or maternal antibodies leading to neonatal thrombocytopenia.

FBC, MPV, blood film Platelet function screen Platelet aggregation Platelet glycoproteins HLA typingSimple bruising  No treatment Epistaxis  Compression  Topical thrombin  Anti-fibrinolytics  Platelet transfusion  rVIIa*  Nasal packing Menorrhagia  Anti-fibrinolytics  Norethisterone (severe)  Oral contraceptive pill  IUD  Uterine packing  Hysterectomy  Iron supplementationDental  Anti-fibrinolytics  Platelets or rVIIa* if extensive Minor surgery  Anti-fibrinolytics  Platelet transfusion  rVIIa* Major surgery  Anti-fibrinolytics  Platelet transfusion pre-op, review need for further transfusions based on response  rVIIa* for first 48 hMother  Epidural anaesthetic contraindicated  Anti-fibrinolytics  Platelet transfusion  rVIIa*  Consider desmopressin post partum if still bleeding  Hysterectomy Newborn†  Avoid ventouse & high forceps  No scalp electrodes  No fetal blood sampling FBC

Bruising is a common symptom and does not need treatment unless there is haemodynamic compromise due to extensive involvement. Patients with epistaxis may respond to local measures like compression, topical thrombin or anti-fibrinolytics and nasal packing (Bellucci & Caen, 2002). Systemic anti-fibrinolytics should be started immediately and continued for 5–7 d. If this is inadequate in achieving haemostasis and there is significant bleeding after 1–2 h, further treatment in the form of platelet transfusion and/or rVIIa may be required. This should be assessed individually for each patient and dictated by clinical response.

Severe menorrhagia is common and is usually associated with a proliferative endometrium caused by oestrogen dominance (Nurden, 2006). In a recent study of 130 Indian women with rare bleeding disorders, 17 of 22 (77%) women with GT and 2 of 3 (67%) women with BSS presented with menorrhagia (Vijapurkar et al, 2009). Menarche may be an especially difficult period consistent with the proliferative oestrogen stimulation of anovulatory cycles. Management needs to be individualized depending on severity of bleeding. The initial therapy of menorrhagia is with anti-fibrinolytics, and failure to control bleeding is then an indication for treatment with hormone supplementation with either progesterone alone or progesterone with oestrogen (Bolton-Maggs et al, 2006). Oral contraceptives are presumed to act by endometrial growth inhibition and improving factor VIII and VWF levels, although the latter effect is not uniform. Severe menorrhagia can be effectively treated by a high dose of progesterone, such as norethisterone 5 mg every 4 h. Severity of symptoms abates within 24 h and the dose can be decreased to 5 mg twice a day and continued for 3 weeks. Menstrual bleeding will result on withdrawal but of reduced severity. Maintenance treatment can then be commenced with combined oral contraceptive pills, such as levonorgestrel 150 and 30 μg ethinyl estradiol (George et al, 1990). Adjuvant therapy with high-dose conjugated estrogens administered intravenously for 24–48 h, followed by high doses of a combined oestrogen-progestin oral preparation has also been used for the attainment of haemostasis in GT (Markovitch et al, 1998). Desmopressin nasal spray is useful in the management of menorrhagia in VWD and haemophilia carriers (Kadir et al, 2002) but menorrhagia in severe platelet disorders does not usually respond to desmopressin alone. Evidence for the use of desmopressin as a single agent in GT is lacking and a combination of treatment modalities may be needed to control menstrual bleeding (Aydinok et al, 2007). Other options include intrauterine devices, uterine packing and surgical therapy like hysterectomy and endometrial ablation in severe cases where there is no further desire for pregnancy. Iron deficiency is a frequent finding and needs to be supplemented. Women with severe menorrhagia should be managed jointly with a gynaecologist.

Intracranial haemorrhage is uncommon but as is the case in any serious haemorrhage, urgent treatment with platelet transfusion and rVIIa is indicated. The management of this situation is complex and close liaison between haematologists and neurosurgeons is required.

Management of surgical procedures

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Surgery in patients with severe platelet function disorders can be potentially life threatening and needs careful planning. All patients should have an individualized management plan for surgical procedures and surgery must be carried out in the same location as the Haemophilia Comprehensive Care Centre. All patients will require screening for HLA and platelet antibodies at routine review and specifically prior to surgical procedures in those who have previously received platelet transfusions (Bolton-Maggs et al, 2006).

Dental procedures

For planned dental extractions, oral anti-fibrinolytics should be started the day before the procedure and continued for 5–7 d. In addition, local haemostatic measures should be employed. Procedures involving milk teeth may be managed as above but more invasive procedures may pose a significant risk of severe bleeding and may require platelet transfusion cover. In GT patients with gpIIb/IIIa or HLA antibodies or platelet refractoriness, recombinant VIIa may be tried in addition to anti-fibrinolytics if the procedure is complicated and more likely to cause excessive haemorrhage (Chuansumrit et al, 2003). In the event of bleeding not responding to repeated doses of rVIIa, platelet transfusion is indicated. The rVIIa International Survey reported successful use of rVIIa in patients with GT as first-line therapy in invasive procedures including 14 dental procedures (Poon et al, 2004). Slight variations exist in dosage and frequency of rVIIa, with reports of 100 μg/kg at 90-min intervals starting prior to the dental extraction (Almeida et al, 2003) or 90 μg/kg given prior to the procedure and then two to three further doses at 90 min to 2-hourly intervals (Bolton-Maggs et al, 2006). Further doses of rVIIa used in conjunction with fibrin glue were successful in achieving haemostasis in dental procedures (Chuansumrit et al, 2003). Patients with severe platelet function disorders other than GT will require platelet transfusion to cover complicated dental procedures with high risk of haemorrhage.

Minor surgery

Minor operative procedures in patients with GT and gpIIb/IIIa or HLA antibodies or platelet refractoriness can be covered with rVIIa starting immediately pre-operatively and continuing 2-hourly doses for the first 12–24 h depending on procedure and bleeding (Bolton-Maggs et al, 2006). If there is no bleeding, the rVIIa dose interval can be increased to 3 hourly and then to 4 hourly doses but the length of treatment depends on the procedure itself, the phenotype of the patient and bleeding. Anti-fibrinolytics should also be started pre-operatively and continued for 7–14 d depending on the procedure performed. Minor surgeries in GT have been successfully performed without the need for platelet transfusion (Poon et al, 1999, 2004) but bleeding not responding to rVIIa may require platelet transfusion and it is advisable to inform the blood transfusion laboratory prior to the procedure and, if transfusion is likely, HLA-matched platelets should be ordered. In GT patients without HLA/gpIIb/IIIa antibodies, the decision to use rVIIa off licence to cover minor surgical procedures must be balanced with the potential for antibody formation with repeated platelet transfusions.

Major surgery

It is important to plan major operative procedures with good communication between the surgeons, haemophilia centre and the transfusion laboratory. At the time of pre assessment, blood sampling for HLA antibodies and anti-platelet antibodies should be performed if this has not already been documented. Pre-operative anti-fibrinolytics should be commenced and continued for 7–14 d. Platelet transfusion (15 ml/kg for children, 1–2 pools for adults) should be given immediately prior to the procedure and further transfusion may be given depending on procedure and clinical need. rVIIa can also be given for 48 h post-operatively as an adjunct.

Management of pregnancy

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Women with platelet function disorders need to be managed in a centre with close collaboration between the haemophilia centre and obstetric department. This includes setting up a detailed management plan for delivery and also a plan for investigation and management of the neonate (Bolton-Maggs et al, 2006). Most women with severe platelet function disorders will need platelet transfusion during child birth and the need for this may sometimes continue for upto a week postpartum (Nurden & George, 2005). Early hospital discharge is therefore rarely possible (Prabu & Parapia, 2006). In families with a history of GT or BSS, consanguineous partnerships should be avoided. In pregnancies where the fetus is at risk of having inherited the platelet function disorder, care must be taken during delivery similar to that in the birth of a haemophiliac. Ventouse extraction and high forceps are contraindicated. Fetal scalp electrode monitoring and fetal blood sampling should also be avoided. Epidural anaesthetics are contraindicated in women with severe bleeding disorders and this must be discussed with the woman during antenatal assessments.

Pregnancy in women with type 1 GT is reported to be rare and this may be related to long term hormone therapy for menorrhagia or planned choice considering the potential risk of severe bleeding at delivery (Léticée et al, 2005). Delivery can be complicated by peri partum and late post partum haemorrhage (Sherer & Lerner, 1999; Léticée et al, 2005). Postpartum haemorrhage may occasionally occur 2–4 weeks after delivery (George et al, 1990; Malhotra et al, 2006). These women are also at risk of miscarriage and intrauterine death (Léticée et al, 2005; Vijapurkar et al, 2009). Reported treatment strategies include plasmaphaeresis aimed at reducing the antibodies (Vivier et al, 1989), steroids (Kashyap et al, 1997), prostaglandins (Capuzzo et al, 1997) and platelet transfusions (Capuzzo et al, 1997; Sherer & Lerner, 1999). Successful delivery of healthy neonates has been reported using single donor platelets in the peri-partum and post-partum period along with oxytocin infusion for effective uterine contraction (Dede et al, 2007). Transplacental passage of gpIIb/IIIa antibodies can result in fetal thrombocytopenia and intracranial haemorrhages have been reported (Boval et al, 2001; Jallu et al, 2005; Léticée et al, 2005). Although successful outcomes have been reported in neonates born to women with gpIIb/IIIa antibodies, fetal/neonatal thrombocytopenia and, specifically, intracranial haemorrhage is clearly a concern. rVIIa has been used in women with GT for persistent post partum haemorrhage despite platelet transfusion resulting in rapid achievement of effective haemostasis (Kale et al, 2004; Sugihara et al, 2008). rVIIa has also been used in women with gpIIb/IIIa antibodies instead of platelet transfusion (Léticée et al, 2005).

Pregnancy in BSS is also complicated by haemorrhage especially in the post-partum period but ante-partum haemorrhage has also been reported (Saade et al, 1991; Prabu & Parapia, 2006). There are few reported successful pregnancies and the majority of them were complicated with bleeding (Michalas et al, 1984; Heslop et al, 1986; Peaceman et al, 1989; Peng et al, 1991; Saade et al, 1991; Avila et al, 1992; Khalil et al, 1998; Fujimori et al, 1999; Kopećet al, 2005; Kriplani et al, 2005; Rahimi et al, 2005). Desmopressin has been used in post-partum haemorrhage in conjunction with other treatments and variable degrees of response were observed (Heslop et al, 1986; Prabu & Parapia, 2006). Caesarean sections were performed for obstetric indications. Hysterectomy was performed in two patients where haemorrhage could not be controlled by medical management (Michalas et al, 1984; Fujimori et al, 1999). The presence of gpIb/IX antibodies resulting in neonatal thrombocytopenia was seen in five neonates, one of whom developed antenatal intracranial haemorrhage (Peng et al, 1991; Fujimori et al, 1999; Uotila et al, 2008). Treatment options include antifibrinolytics, platelet transfusions, intravenous desmopressin post partum, rVIIa and supportive care.

Conclusions

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References

Patients with severe platelet function disorders need to be managed in specialist Haemophilia centres and all elective procedures need to be planned. It is advisable to check for HLA and anti-platelet antibodies early and monitor regularly. Minor bleeding may be treated with local measures and anti-fibrinolytic drugs but invasive procedures will need to be covered with rVIIa and/or platelet transfusion. The role of rVIIa in patients with GT in the absence of HLA/platelet antibodies, in order to prevent sensitization or when there is delay in availability of suitable matched platelets, is less clear and this agent is not licensed for use in such situations. Desmopressin may be useful in certain patients with storage pool disorders and BSS but is of limited benefit in GT. Practice and recommendations vary with regards to the use of HLA selected platelets in patients in whom HLA and anti-platelet antibodies are not demonstrated. We recommend HLA-matched platelets in all patients with severe platelet function disorders.

References

  1. Top of page
  2. Summary
  3. Bernard–Soulier Syndrome (BSS)
  4. Glanzmann Thrombasthenia (GT)
  5. General management of severe platelet function disorders
  6. Agents used in the management of platelet function disorders
  7. Management of spontaneous and traumatic bleeds ()
  8. Management of surgical procedures
  9. Management of pregnancy
  10. Conclusions
  11. References
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